EP0388309B1 - 1H,3H,7-pyrrolo [1,2-c] thiazolecarboxamides, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

New derivatives of formula (I) in which R1=H, halogen, alkyl, alkyloxy, CF3, NH2, alkylamino, dialkylamino, OH, CH, phenyl or phenoxy, Ar=phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, thienyl, thieno[2,3-b]thienyl or thieno[3,2-b]thienyl (these groups optionally substituted with halogen, alkyl, alkyloxy, CF3, NH2, alkylamino, dialkylamino, OH or CN), p=0, 1 or 2, and A-either Z=valency bond and R2=H B-or Z=valency bond and R2=pyridyl, quinuclidinyl, 3-pyrrolidinyl, 3- or 4-piperidyl (these groups optionally being substituted with alkyl, hydroxyalkyl, phenyl or phenylalkyl) C-or Z=alkylene radical (1 to 4C) and R2=2-, 3- or 4-pyridyl, 3-quinuclidinyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidyl (optionally substituted with alkyl, hydroxyalkyl, phenyl or phenylalkyl) or R2=CON(R3)(R4) where a) either R3 and R4 form a piperazine optionally substituted with alkyl, hydroxyalkyl, pyridyl, phenyl or phenylalkyl, b) or R3=H, alkyl, phenyl or phenylalkyl, or (CH2)nN(R5) (R6) where 1<n<4 and R5 and R6=H, alkyl, phenyl, phenylalkyl, or R5 and R6 form a morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine ring, (optionally substituted with alkyl, hydroxyalkyl, pyridyl, phenyl, phenylalkyl or phenylcarbonyl), and R4=(CH2)nN(R5)(R6) defined as above, D- or Z=alkylene (1 to 4C) and R2=N(R3) (R4) or N(R5)R6) where R3, R4, R5 and R6 are defined as above in C b), on the understanding that the alkyls contain 1 to 4C in a straight or branched chain and that the invention relates to the racemates, the enantiomers and mixtures thereof, the diastereoisomers, pure or mixed, and the E and Z isomers, as well as to the salts of these products. <IMAGE> (I)

Description

dans laquelle R₁ représente un atome d'hydrogène ou d'halogène ou un radical alcoyle, alcoyloxy, trifluorométhyle, amino, alcoylamino, dialcoylamino, hydroxy, cyano, phényle ou phénoxy, Ar représente un radical phényle, naphtyle, pyridyle, quinolyle, isoquinolyle, thiényle, thiéno[2,3-b] thiényle-2 ou thiéno[3,2-b] thiényle-2, ces radicaux pouvant éventuellement porter un ou plusieurs substituants choisis parmi les atomes d'halogène ou les radicaux alcoyle, alcoyloxy, trifluorométhyle, amino, alcoylamino, dialcoylamino, hydroxy ou cyano, p représente un nombre entier égal à zéro, un ou deux et

• A- soit Z représente une liaison de valence et R₂ représente un atome d'hydrogène,
• B- soit Z représente une liaison de valence et R₂ représente un radical pyridyle-2 ou -4, quinuclidinyle-3, pyrrolidinyle-3, pipéridyle-3 ou -4, ces deux derniers radicaux pouvant être éventuellement substitués sur l'atome d'azote par un radical alcoyle, hydroxyalcoyle, phényle ou phénylalcoyle,
• C- soit Z représente un radical alcoylène contenant 1 à 4 atomes de carbone et R₂ représente un radical pyridyle-2, -3 ou -4, quinuclidinyle-3, pyrrolidinyle-2 ou -3, pipéridyle-2, -3 ou -4, ces deux derniers radicaux pouvant être substitués sur l'atome d'azote par un radical alcoyle, hydroxyalcoyle, phényle ou phénylalcoyle ou bien R₂ représente un radical de formule générale :
  
  dans laquelle :
  • a) soit R₃ et R₄ forment ensemble avec l'atome d'azote auquel ils sont liés un cycle pipérazine éventuellement substitué sur le deuxième atome d'azote par un radical alcoyle, hydroxyalcoyle, pyridyle, phényle ou phénylalcoyle,
  • b) soit R₃ représente un atome d'hydrogène ou un radical alcoyle, phényle ou phénylalcoyle ou un radical de formule générale :
    
    dans laquelle n représente un nombre entier compris entre 1 et 4 et R₅ et R₆, identiques ou différents, représentent un atome d'hydrogène ou un radical alcoyle, phényle, phénylalcoyle, ou bien R₅ et R₆ forment ensemble avec l'atome d'azote auquel ils sont liés un cycle morpholine, thiomorpholine, pyrrolidine, pipéridine ou pipérazine dont le second atome d'azote peut être éventuellement substitué par un radical alcoyle, hydroxyalcoyle, pyridyle, phényle, phénylalcoyle ou phénylcarbonyle, et R₄ représente un radical de formule générale (III) défini comme précédemment, étant entendu que les définitions de n, R₅ et R₆ dans les symboles R₃ et R₄ peuvent être identiques ou différents,
• D- soit Z représente un radical alcoylène contenant 1 à 4 atomes de carbone et R₂ représente un radical de formule générale :
  
  dans lesquelles R₃, R₄, R₅ et R₆ sont définis comme précédemment en C a) et b), étant entendu que les radicaux alcoyle et portions alcoyle contiennent 1 à 4 atomes de carbone en chaîne droite ou ramifiée et que l'invention concerne les produits racémiques, les énantiomères dus à la présence d'un carbone asymétrique en position 3 du cycle pyrrolothiazole, les mélanges de ces énantiomères, les diastéréoisomères purs ou en mélange dus à la présence éventuelle d'un autre centre chiral, les isomères E et Z (encore appelés syn et anti) et leurs mélanges provenant de la présence de la fonction oxime C=NO-Z-R₂, ainsi que les sels pharmaceutiquement acceptables des produits de formule (I) ainsi définie.

The present invention relates to new derivatives of 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 of general formula:

in which R₁ represents a hydrogen or halogen atom or an alkyl, alkyloxy, trifluoromethyl, amino, alkylamino, dialkoylamino, hydroxy, cyano, phenyl or phenoxy radical, Ar represents a phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl radical, thienyl, thieno [2,3-b] thienyl-2 or thieno [3,2-b] thienyl-2, these radicals possibly being able to carry one or more substituents chosen from halogen atoms or alkyl, alkyloxy, trifluoromethyl radicals , amino, alkyllamino, dialcoylamino, hydroxy or cyano, p represents an integer equal to zero, one or two and

• A- either Z represents a valence bond and R₂ represents a hydrogen atom,
• B- either Z represents a valence bond and R₂ represents a pyridyl-2 or -4, quinuclidinyl-3, pyrrolidinyl-3, piperidyl-3 or -4 radical, the latter two radicals possibly being substituted on the atom nitrogen by an alkyl, hydroxyalkyl, phenyl or phenylalkyl radical,
• C- either Z represents an alkylene radical containing 1 to 4 carbon atoms and R₂ represents a pyridyl-2, -3 or -4, quinuclidinyl-3, pyrrolidinyl-2 or -3, piperidyl-2, -3 or -4 , these last two radicals which may be substituted on the nitrogen atom by an alkyl, hydroxyalkyl, phenyl or phenylalkyl radical or else R₂ represents a radical of general formula:
  
  in which :
  • a) either R₃ and R₄ form together with the nitrogen atom to which they are linked a piperazine ring optionally substituted on the second nitrogen atom by an alkyl, hydroxyalkyl, pyridyl, phenyl or phenylalkyl radical,
  • b) either R₃ represents a hydrogen atom or an alkyl, phenyl or phenylalkyl radical or a radical of general formula:
    
    in which n represents an integer between 1 and 4 and R₅ and R₆, identical or different, represent a hydrogen atom or an alkyl, phenyl, phenylalkyl radical, or else R₅ and R₆ form together with the nitrogen atom to which they are linked a morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine ring, the second nitrogen atom of which may be optionally substituted by an alkyl, hydroxyalkyl, pyridyl, phenyl, phenylalkyl or phenylcarbonyl radical, and R₄ represents a radical of general formula ( III) defined as above, it being understood that the definitions of n, R₅ and R₆ in the symbols R₃ and R₄ may be the same or different,
• D- or Z represents an alkylene radical containing 1 to 4 carbon atoms and R₂ represents a radical of general formula:
  
  in which R₃, R₄, R₅ and R₆ are defined as above in C a) and b), it being understood that the alkyl radicals and alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain and that the invention relates to the products racemic, enantiomers due to the presence of an asymmetric carbon in position 3 of the pyrrolothiazole ring, mixtures of these enantiomers, pure or mixed diastereoisomers due to the possible presence of another chiral center, the E and Z isomers ( also called syn and anti) and their mixtures originating from the presence of the oxime function C = NO-Z-R₂, as well as the pharmaceutically acceptable salts of the products of formula (I) thus defined.

dans laquelle les symboles p, R₁ et Ar sont définis comme précédemment.According to the invention, the products of general formula (I) can be prepared by the action of a hydroxylamine of general formula:

H₂NO-Z-R₂ (VI)


in which Z and R₂ are defined as above, on a ketone of general formula:

in which the symbols p, R₁ and Ar are defined as above.

In practice, the hydroxylamine of general formula (VI) is used in the form of the hydrochloride and it is operated in an organic solvent such as pyridine or a low molecular weight alcohol such as propanol in the presence of an acid acceptor such as an alkali metal carbonate at a temperature between 20 ° C and the reflux temperature of the reaction mixture.

The products of general formula (VI) can be prepared by application or adaptation of methods described in the literature.

dans laquelle R₁ et Ar sont définis comme précédemment.The products of general formula (VII) in which p is equal to 1 or 2 can be obtained by oxidation of a product of general formula (VII) in which p is equal to 0, that is to say a product of general formula:

in which R₁ and Ar are defined as above.

The oxidation can be carried out for example by using an agent commonly used to pass from a sulphide to a sulphoxide or to a sulfone by operating in an appropriate solvent. For example, hydrogen peroxide can be used in acetone or acetic acid, an alkaline periodate in an alcohol or acetonitrile, a carboxylic peracid (peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, p-nitroperbenzoic acid or perphthalic acid) in an ether (dioxane, tetrahydrofuran, diethyl ether), or a chlorinated solvent (dichloromethane, 1,2-dichloroethane), acetic acid or a mixture of these solvents. The reaction is generally carried out at a temperature between -10 ° C and + 20 ° C.

It is particularly advantageous to operate in dichloromethane in the presence of m-chloroperbenzoic acid, at a temperature between 0 and 20 ° C.

When it is desired to obtain the sulfoxide, it is necessary to carry out the reaction with an equivalent of oxidizing agent. When it is desired to obtain the sulfone, it is necessary to use at least two equivalents of oxidizing agent. The actual oxidation reaction is carried out in the presence of at least one equivalent of acid such as methanesulfonic acid, at a temperature in the region of 20 ° C.

The products of general formula (VII) in which p is equal to zero, that is to say the products of general formula (VII _A ) can be prepared according to the method described in the European patent application published under number 0 253,711.

dans laquelle p, R₁ et Ar sont définis comme précédemment.According to the invention, the products of general formula (I) in which the symbols are defined as above in B, C or D can be prepared by the action of a product of general formula:

XZ-R₂ (VIII)


in which Z and R₂ are defined as above and X represents a halogen atom such as a chlorine, bromine or iodine atom, or a reactive ester residue such as mesyloxy or tosyloxy, on a product of formula general (I) defined as above in A, that is to say a product of general formula:

in which p, R₁ and Ar are defined as above.

It is generally carried out in an organic solvent such as dimethylformamide at a temperature in the region of 20 ° C. in the presence of a condensing agent such as an alkaline hydride such as sodium hydride, or in a low molecular weight alcohol such as ethanol or t-butanol in the presence of an alkali metal alcoholate such as sodium ethylate or potassium t-butoxide at reflux.

The products of general formula (I _A ) can be prepared by the action of a product of general formula (VI) in which Z represents a valence bond and R₂ represents a hydrogen atom, on a product of general formula (VII) as said before.

The products of general formula (I _A ) in which p is equal to 1 or 2 can also be prepared by oxidation of a product of general formula (I) in which p is equal to zero, R₁ and Ar are defined as above in A, that is to say a product of general formula:

The oxidation can be carried out as has been said previously for the oxidation of a product of general formula (VII _A ).

sous forme R ou S ou leurs mélanges, sur une oxime de formule générale :

dans laquelle Ar, Z, R₁ et R₂ sont définis comme précédemment, sous forme E ou Z ou leurs mélanges.According to the invention, the products of general formula (I) in which p is equal to 0 can also be obtained by the action of a derivative of chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2 -c] thiazole of general formula:

in R or S form or their mixtures, on an oxime of general formula:

in which Ar, Z, R₁ and R₂ are defined as above, in the form E or Z or their mixtures.

Generally, the condensation is carried out under the usual conditions for the preparation of amides by the action of an acid chloride on a primary amine.

dans laquelle Ar et R₁ sont définis comme précédemment, sous forme E ou Z ou leurs mélanges.The product of general formula (X) can be obtained by the action of a product of general formula (VIII) on an oxime of general formula:

in which Ar and R₁ are defined as above, in the form E or Z or their mixtures.

Generally the reaction is carried out in the presence of an alkali metal hydride such as sodium hydride by operating in an organic solvent such as dimethylformamide at a temperature in the region of 20 ° C.

The oxime of general formula (XI) in form E or Z can be obtained by separation, for example by chromatography, of the mixture of forms E and Z.

dans laquelle Ar et R₁ sont définis comme précédemment.The mixture of forms E and Z of the oxime of general formula (XI) can be obtained by the action of a hydroxylamine salt (hydrochloride, tosylate) on a product of general formula:

in which Ar and R₁ are defined as above.

Generally, one operates in an organic solvent such as pyridine or a low molecular weight alcohol such as propanol in the presence of an acid acceptor such as an alkali metal carbonate such as sodium carbonate at a temperature between 20 ° C and the boiling temperature of the reaction mixture.

The product of general formula (X) can also be obtained by the action of a hydroxylamine of general formula (VI) on a ketone of general formula (XII) under the conditions described above for the action of a hydroxylamine of general formula ( VI) on a ketone of general formula (VII).

The products of general formula (I) in which p is equal to 1 can be obtained by oxidation of a product of general formula (I) in which p is equal to 0.

Generally the oxidation is carried out by means of an oxidizing agent such as hydrogen peroxide or m.chloroperbenzoic acid. It is particularly advantageous to use hydrogen peroxide.

When, in the present invention, reference is made to a product determined by its chemical name, it is understood that in the absence of specific specifications, reference is always made to the racemic product or to the mixture of syn and anti isomers.

The products of general formula (I) in which the substituents Ar and OZ-R₂ of the oxime function are in syn or anti position (E or Z) can be prepared from the corresponding mixtures by conventional conventional methods such as liquid chromatography high performance (HPLC).

The products of general formula (I) may exist in racemic form or in the form of pure enantiomers because the carbon atom in position 3 of the pyrrolothiazole ring is asymmetric. To obtain the products of general formula (I) in the form of pure enantiomers, it is advantageous to use the methods described above using a product of general formula (VII) already split; this can be prepared according to the method described in the European patent application published under the number 0 253 711.

It is understood for those skilled in the art that, for the implementation of the methods described above, it may be necessary to introduce protective groups at the level of certain functions present in the radicals Ar, R₁ and R₂ of the various products used. artwork. The protective group can then be eliminated at the most opportune moment of the synthesis. Thus, when in the Ar, R₁ and / or R₂ radical an amino or alkylamino function is present, this can be protected for example by a t-butyloxycarbonyl radical and then released after reaction by means of an aqueous acid, for example at using an aqueous solution of hydrochloric acid, or better still using an acetic solution of hydrochloric gas. When in the radical Ar, R₁ and / or R₂ is present a hydroxy function, this can be advantageously protected in the form of a tetrahydropyranyloxy or methoxymethyloxy radical, then released after reaction by hydrolysis.

The new products of general formula (I) can be purified by the usual known methods, for example by crystallization or by chromatography.

The new products of general formula (I) can be converted into addition salts with acids by reaction with an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. The salt precipitates, possibly after concentration of its solution; it is separated by filtration or decantation.

The new products according to the invention and their pharmaceutically acceptable salts have advantageous properties associated with low toxicity. They are usually active at concentrations below 0.5 nM in the test for measuring the inhibitory activity in vitro against platelet aggregation induced by O-octadecyl-1 O-acetyl-2 ns-glycerophosphorylcholine- 3 (PAF-acether), according to the technique of GVR BORN et al., J. Physiol., 168 , 178 (1963).

Their toxic dose (expressed by the DL₅₀) in mice is generally between 300 and 900 mg / kg orally.

For therapeutic use, use may be made of the new products of formula (I) as such or, where appropriate, in the form of pharmaceutically acceptable salts, that is to say non-toxic at the doses of use .

As pharmaceutically acceptable salts, there may be mentioned addition salts with mineral acids such as hydrochlorides, sulfates, nitrates, phosphates, or organic salts such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isethionates, theophillineacetates, salicylates , phenolphthalinates, methylene-bis-b-oxynaphtoates or substitution derivatives of these compounds.

The following examples show how the invention can be put into practice.

EXAMPLE 1

To a suspension of 21.27 g of (+) - N- (3-benzoyl-phenyl) (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 250 cm3 of propanol-1 , 5.30 g of sodium carbonate and 6.95 g of hydroxylamine hydrochloride are added. The suspension is heated to reflux, with stirring for 2 hours. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The residue is taken up in 250 cm3 of distilled water and crystallization is initiated. The crystals that appear are separated by filtration, washed 4 times with 300 cm 3 in total of distilled water and then air dried. 22.04 g of product melting at 210 ° C. are thus obtained. 2 g of this product are dissolved in 80 cm3 of boiling propanol-1. The solution obtained is filtered hot and the filtrate is cooled to a temperature close to 0 ° C for 48 hours. The crystals that appear are separated by filtration, washed three times with 10 cm 3 in total of absolute ethanol and then dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. 1.74 g of (+) - N- [α- (hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 are thus obtained (mixture of the forms E and Z) in the form of white crystals melting at 151-155 ° C.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is prepared according to the method described in the European patent application published under n ° 0 253 711.

EXAMPLE 2

To a mixture of 325 mg of a 50% dispersion of sodium hydride in petroleum jelly oil and 4 cm3 of anhydrous N, N-dimethylformamide, is added, under a stream of nitrogen, in about five minutes, a solution of 2 g of (+) - N- [α- (hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 10 cm3 of anhydrous N, N-dimethylformamide. After a quarter of an hour of stirring at room temperature, a solution of 1.19 g of (3-chloro-propyl) -1 phenyl-4 piperazine in 3 cm 3 of N, N-dimethylformamide is added over approximately 2 minutes. the solution obtained for 16 hours at room temperature. 150 cm3 of distilled water are then added and crystallization begins. After 3 hours of stirring at room temperature, the crystals obtained are separated by filtration, washed 3 times with 45 cm 3 in total of distilled water and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 20 ° C. 2.74 g of product are thus obtained. This product is dissolved in 15 cm3 of acetone. 0.77 g of oxalic acid is added to the solution obtained and stirred for 3 hours at room temperature. The crystals obtained are separated by filtration, washed 4 times with 20 cm 3 in total of acetone and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. 2.74 g of (+) - N - {{α - [(4-phenyl-piperazinyl-1) -3 acid dioxalate are thus obtained propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of cream crystals melting at 130 ° C .

(3-Chloro-propyl) -1 phenyl-4 piperazine can be prepared according to CB POLLARD, J. Org. Chem. 24 , 764, 1958.

The (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

EXAMPLE 3

To a solution of 2 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 10 cm3 of anhydrous N, N-dimethylformamide, 0.44 g of a 50% dispersion of sodium hydride in oil is added at room temperature, under a stream of nitrogen and with stirring. petroleum jelly. A solution of 0.72 g of 3-dimethylamino-1-chloro-propane hydrochloride in 20 cm3 of anhydrous N, N-dimethylformamide is then added in approximately 1 minute. The solution is then stirred for 6 hours at room temperature, then added with 10 cm 3 of distilled water. The solvent is evaporated under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. The residue is taken up in 100 cm3 of acetone. After 15 minutes of stirring at room temperature, the solid is separated by filtration and washed twice with 40 cm 3 in total of acetone. The filtrate is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 2.5 g of an orange residue are obtained. This product is chromatographed on a column 3 cm in diameter containing 65 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and methanol (50-50 by volume) under a pressure of 0.5 bar (51 kPa), collecting 25 cm3 fractions. The first 19 fractions are eliminated. The following 31 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.3 g of product are thus obtained. This product is dissolved in 40 cm3 of ethyl ether. The To this solution is added 1.65 cm3 of a 4N solution of hydrochloric gas in ethyl ether and stirred at a temperature in the region of 20 ° C for 15 minutes. The crystals obtained are separated by filtration and washed 4 times with 50 cm 3 in total of ethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. 1.35 g of (+) - N- {α - [(3-dimethylamino-propoxyimino) benzyl] -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c dihydrochloride are thus obtained. ] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of cream crystals melting at 140 ° C.

The (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

EXAMPLE 4

To a solution of 2.64 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, (mixture forms E and Z) in 10 cm3 of anhydrous N, N-dimethylformamide, 0.86 g of a 50% dispersion of sodium hydride in 1 is added at room temperature, under a stream of nitrogen and with stirring petroleum jelly, then, in small fractions, 1.24 g of (3-chloro-propyl) hydrochloride -1 piperidine in about 5 minutes. The solution is then stirred for 48 hours at a temperature in the region of 20 ° C. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa). 4.85 g of a pasty orange residue are thus obtained which is chromatographed on a column 4 cm in diameter containing 150 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and methanol (70-30 by volume) under a pressure of 0.5 bar (51 kPa), collecting 80 cm3 fractions. The first 10 fractions are eliminated. The following 31 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 2.8 g of product are thus obtained. This product is dissolved in 30 cm3 of ethyl acetate. The insoluble material is separated by filtration and the filtrate is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C. The 2.70 g of product obtained are dissolved in 15 cm3 of an aqueous solution of 1N hydrochloric acid. The solution obtained is filtered and then lyophilized. The 3.2 g thus obtained are dissolved in 50 cm3 of distilled water. The solution obtained is brought to a pH in the region of 8 by adding sodium bicarbonate and is then extracted 3 times with 50 cm 3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 35 ° C. 2 g of a beige meringue are thus obtained. This product is chromatographed on a column 3 cm in diameter containing 65 g of silica (0.02-0.045 mm). Eluted with ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting fractions of 250 cm3. The first fraction is eliminated. The following 12 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.3 g of product are thus obtained which are redissolved in 3 cm3 of acetonitrile. To the solution obtained is added 20 cm 3 of ethyl ether and then 2 cm 3 of a 4N solution of hydrochloric gas in ethyl ether and stirred at a temperature in the region of 20 ° C for 15 minutes. The crystals obtained are separated by filtration and washed 4 times with 50 cm 3 in total of ethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. 1.3 g of (+) - N - {[α- (3-piperidino-propoxyimino) benzyl] -3 phenyl} (3-pyridyl) -3 1H, 3H pyrrolo [1,2-c] dihydrochloride are thus obtained. thiazolecarboxamide-7 (mixture of forms E and Z), in the form of cream crystals melting at 142 ° C.

The (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

EXAMPLE 5

To a solution of 5.9 g of (+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 100 cm3 of propanol-1 heated to reflux, 3.1 g of 2-morpholino ethoxyamine hydrochloride and 1.5 g of sodium carbonate. The suspension is stirred for 5 hours and 30 minutes at reflux and then brought back to a temperature in the region of 20 ° C. The insoluble material is separated by filtration and washed with 20 cm 3 of propanol-1. The filtrate is concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 9 g of a pasty orange product are thus obtained. This product is chromatographed on a column 6 cm in diameter containing 1 kg of acid activated alumina (0.050-0,200 mm). Eluted with a mixture of ethyl acetate and cyclohexane (50-50 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 500 cm3. The first 20 fractions are eliminated; the next 10 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 8.1 g of product are thus obtained. This product is chromatographed on a column 3 cm in diameter containing 125 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and methanol (90-10 by volume) under a pressure of 0.5 bar (51 kPa), collecting 25 cm3 fractions. The first 19 fractions are eliminated the following 7 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 4 g of a yellow meringue are thus obtained. The product is chromatographed on a column 6 cm in diameter containing 65 g of neutral alumina (0.100-0.125 mm). Eluted with a mixture of ethyl acetate and cyclohexane (20-80 by volume), collecting fractions of 300 cm3. The first 3 fractions are eliminated; the following 3 are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). 2 g of product are obtained in the form of a white meringue. This product is chromatographed on a column 4 cm in diameter containing 25 g of neutral alumina (0.100-0.125 mm). Eluted with a mixture of ethyl acetate and cyclohexane (50-50 by volume), collecting fractions of 100 cm3. The first 9 fractions are eliminated; the next 7 are concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.55 g of product are obtained. 850 mg of this product is dissolved in 15 cm3 of an aqueous solution of 0.21N methanesulfonic acid. The aqueous solution obtained is lyophilized. 0.98 g of (+) - N - {[α- (2-morpholino-ethoxyimino) benzyl] -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c dimethanesulfonate are thus obtained. ] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of light yellow crystals melting at 122 ° C.

2-morpholino ethoxyamine hydrochloride can be prepared according to D. FAVARA et al., Il Farmaco, Ed. Sci., 42 , 697, 1987.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in the European patent application published under number 0 253,711.

EXAMPLE 6

To a solution of 9.3 g of (+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 160 cm3 of propanol-1 heated to a temperature in the region of 75 ° C., 6.2 g of (4-methyl-piperazinyl-1) -3-propoxyamine hydrochloride and 3.8 g of sodium carbonate are added, with stirring. The suspension obtained is heated to reflux for 29 hours then the reaction mixture is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. The residue obtained is taken up in a mixture of 300 cm3 of water and 300 cm3 of methylene chloride. The organic phase is separated and the aqueous phase is extracted twice with 600 cm3 in total of methylene chloride. The organic extracts are combined, washed twice with 600 cm3 in total of distilled water, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature. 50 ° C. 14.3 g of crude product are thus obtained. This product is chromatographed on a column 6 cm in diameter containing 450 g of silica (0.02-0.045 mm). Eluted with a mixture of methylene chloride and methanol (50-50 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 500 cm3. The first 7 fractions are eliminated. The following 13 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C. 7.2 g of product are thus obtained. This product is combined with 0.8 g of another sample from a previous preparation and is dissolved in 200 cm3 of acetone. The solution obtained is added, at a temperature in the region of 20 ° C, to a solution of 2.5 g of oxalic acid in 100 cm3 of acetone. The suspension obtained is stirred at a temperature in the region of 20 ° C for 1 hour and 30 minutes; the crystals which appear are separated by filtration, washed 3 times with 150 cm3 in total of acetone then 2 times with 100 cm3 in total of ethyl ether and finally dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. 9.1 g of (+) - N - {(α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H acid dioxalate are thus obtained. -pyrrolo [1,2-c] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of white crystals melting at 190 ° C.

1.16 g of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo are dissolved. , 2-c] thiazolecarboxamide-7, in base form, in 10 cm3 of ethyl acetate. The solution obtained is treated with 50 mg of bleaching black and filtered. The insoluble material is washed with 10 cm 3 of ethyl acetate. 1 cm3 of 4N hydrochloric ether is added to the filtrate and the mixture is stirred at a temperature in the region of 20 ° C for 15 minutes. The crystals which appear are separated by filtration, washed 3 times with 9 cm 3 in total of ethyl acetate and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 1.27 g of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H- dihydrochloride are thus obtained. pyrrolo [1,2-c] thiazolecarboxamide-7, as a mixture of forms E and Z, in the form of cream crystals melting at 150-155 ° C.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in the European patent application published under number 0 253,711.

The (4-methyl-1 piperazinyl) -3-propoxyamine hydrochloride can be obtained in the following way: A solution of 5.7 g of N - [(4-methyl-piperazinyl-1) - is heated at reflux for 3 hours - 3 propoxy] phthalimide in 30 cm3 of hydrochloric acid 6N. After 18 hours of stirring at a temperature in the region of 20 ° C, the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature of around 60 ° C. 6 g of crude product are thus obtained which are resuspended in 30 cm3 of ethanol. The crystals which appear are separated by filtration, washed 3 times with 45 cm3 in total of ethanol then 3 times with 75 cm3 in total of ethyl ether and finally dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. 3.4 g of (4-methyl-piperazinyl-1) -3-propoxyamine hydrochloride are thus obtained in the form of cream crystals, melting at 240 ° C.

The N - [(4-methylpiperazinyl) -3 propoxy] phthalimide can be obtained as follows: A solution of 8.4 g of (3-hydroxypropyl) -1 methyl-4 piperazine, 8.2 g of N-hydroxy phthalimide and 13.1 g of triphenylphosphine in 120 cm 3 of tetrahydrofuran is cooled to a temperature in the region of 0 ° C. and 10.1 g of ethyl azodicarboxylate is added over 30 minutes. The solution obtained is stirred at a temperature in the region of 20 ° C for 18 hours and then concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. The crude oil obtained is chromatographed on a column 5 cm in diameter containing 400 g of silica (0.063-0.2 mm). Eluted with mixtures of ethyl acetate and methanol, collecting 500 cm 3 fractions. The first 5 fractions from the elution with pure ethyl acetate and the next 5 fractions from the elution with a mixture of ethyl acetate and methanol (70-30 by volume) are eliminated. The next fraction from the elution with a mixture of ethyl acetate and methanol (70-30 by volume), the next 5 fractions from the elution with a mixture of ethyl acetate and methanol ( 50-50 by volume) and the following 2 fractions originating from the elution with pure methanol are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 11.4 g of N - [(methyl-4 piperazinyl-1) -3 propoxy] phthalimide are thus obtained in the form of a red oil (Rf = 0.2; chromatography on a thin layer of silica eluent: acetate ethyl-methanol 50-50 by volume).

The separation of forms E and Z can be carried out as follows: 50 mg of (+) - N - {{α [(methyl-4 piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl) is dissolved -3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, (mixture of forms E and Z), previously obtained in 2 cm3 of a mixture of acetonitrile and water (50-50 in volumes). The solution obtained is injected onto a chromatography column 25 cm long and 2 cm in diameter filled with a stationary phase of silica grafted with C18 [ULTRABASE silica (registered name of the French Society for Chromatography on a column at Neuilly-Plaisance, France)]. The column is eluted with a mixture of acetonitrile, water and triethylamine (40-60-0.5 by volume) at a flow rate of 5 cm3 per minute. The eluates are analyzed by ultraviolet absorptiometry at 270 nm. The two isomers are detected at the respective retention times of 90 and 110 minutes. The eluates containing the sought products are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C and dried under reduced pressure (1 mm of mercury; 0.7 kPa) at 20 ° C overnight. 14 mg of form A and 18 mg of form B of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) are thus obtained. 3 1H, 3H pyrrolo [1,2-c] thiazolecarboxamide-7, in the form of acid dioxalate.

150 mg of form A of the acid dioxalate of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, obtained by repeating the previous operation, are dissolved in 5 cm3 of 1N sodium hydroxide. The solution is extracted 3 times with 25 cm 3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The 145 mg of product obtained are dissolved in 5.23 cm3 of 0.1N hydrochloric acid and the solution obtained is lyophilized. This gives 153 mg of (+) - N - {{α - [(4-methyl-1-piperazinyl) -3 propoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H pyrrolo [1,2 -c] thiazolecarboxamide-7, form A, as dihydrochloride.

120 mg of form B of the acid dioxalate of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, obtained by repeating the previous operation, are dissolved in 5 cm3 of 1N sodium hydroxide. The solution is extracted 3 times with 30 cm3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The 100 mg of product obtained are dissolved in 3.6 cm3 of 0.1N hydrochloric acid and the solution obtained is lyophilized. 108 mg of (+) - N - {{α - [(4-methyl-1-piperazinyl) -3 propoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H pyrrolo [1,2 are thus obtained -c] thiazolecarboxamide-7, form B, in the dihydrochloride state.

The two forms were identified by their R.M.N. proton (200 MHz, DMSO, d in ppm, J in Hz) with the following specifications: S = singlet, D = doublet, T = triplet, Mf = solid, Mt = multiplet, DD = double doublet, DT = double triplet .

Form A:

2.2 (Mf, 2H: -CH₂-C H ₂-CH₂-); 2.86 (S, 3H: .NCH₃) 3.24 (Mf, 2H: -CH₂-C H ₂-N,); 3.3 to 3.9 (Mt, 8H: .NCH₂- of piperazine); 4.24 (T, J = 7.2H: -OCH₂-); 4.45 and 4.63 (D, J = 15 and DD, J = 15 and 1.1 H each: CH₂ of pyrrolothiazole); 6.74 (D, J = 2.5, 1H: CH 6 of pyrrolothiazole); 6.86 (D, J = 1.1 H: CH 3 in pyrrolothiazole); 7.09 (DT, J = 8.1 H, para-aromatic of -NH-CO-); 7.11 (D, J = 2.5, 1H: CH at 5 of pyrrolothiazole); 7.4 to 7.6 (Mt, 6H: aromatic) 7.8 (Mt, 2H: H in 5 of pyridine and aromatic in ortho of -NH-CO- and .C = N-); 7.92 (D wide, J = 8, 1H: 4H of pyridine); 8.01 (DT, J = 8.1H: aromatic in ortho of -NH-CO-); 8.71 (broad S, 1H: 2 H pyridine); 8.78 (D wide, J = 5.1H: H at 6 of pyridine); 9.84 (S, 1H: -CONH-); ∼11.8 (spread Mf, ∼1H: .NHs-).

Form B:

2.19 (Mt, 2H: -CH₂-C H ₂-CH₂); 2.87 (S, 3H: .NCH₃); 3.20 (Mf, 2H: -CH₂-C H ₂-N,); 3.3 to 3.9 (Mt, 8H: .NCH₂- of piperazine); 4.23 (T, J = 7.2H: -OCH₂-); 4.44 and 4.63 (D, J = 15 and DD, J = 15 and 1.1 H each: CH₂ of pyrrolothiazole); 6.73 (D, J = 2.5, 1H: CH 6 of pyrrolothiazole); 6.86 (D, J = 1.1 H: CH 3 in pyrrolothiazole); 7.08 (D, J = 2.5, 1H: CH 5 of pyrrolo-thiazole); 7.08 (Mt, 1H: aromatic para -NH-CO-); 7.3 to 7.65 (Mt, 6H: aromatics); 7.77 (DD, J = 8 and 5, 1H: H at 5 of pyridine); 7.85 to 8.05 (Mt, 3H: aromatic in ortho of -NH-CO- and in 4 of pyridine); 8.7 (broad S, 1H: 2 H pyridine); 8.77 (D, J = 5.1H: H at 6 of pyridine); 9.79 (S, 1H: -CONH-); ∼11.7 (spread Mf, ∼1H: .NHs-).

EXAMPLE 7

To a solution of 9.15 g of (+) - N- (benzoyl-3 phenyl) (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 110 cm3 of propanol-1 heated to a temperature in the region of 80 ° C., 3.8 g of 2-dimethylaminoethoxyamine dihydrochloride and 2.3 g of sodium carbonate are added, with stirring. The suspension obtained is heated at reflux for 8 hours then, after addition of 0.23 g of sodium carbonate, for an additional 8 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. After cooling, the residue obtained is taken up in a mixture of 250 cm3 of water and 250 cm3 of methylene chloride. The organic phase is separated and the aqueous phase is extracted twice with 500 cm 3 in total of methylene chloride. The organic extracts are combined, washed twice with 500 cm3 in total of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C. 11 g of crude product are thus obtained. This product is chromatographed on a column 6 cm in diameter containing 450 g of silica (0.02-0.045 mm). Elution is carried out with mixtures of methylene chloride and methanol under a pressure of 0.5 bar (51 kPa), collecting 500 cm 3 fractions. The first 4 fractions from the elution with a mixture of methylene chloride and methanol (90-10 by volume) are eliminated. The next 9 fractions from the elution with a mixture of methylene chloride and methanol (90-10 by volume) and the next 7 fractions from the elution with a mixture of methylene chloride and methanol (80-20 by volume) are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 5.9 g of product are thus obtained. 4 g of this product are chromatographed on a column of silica 6 cm in diameter containing 450 g of silica (0.02-0.045 mm). Elution is carried out with mixtures of ethyl acetate and methanol under a pressure of 0.5 bar (51 kPa), collecting 500 cm 3 fractions. The first 10 fractions from elution with a mixture of ethyl acetate and methanol (50-50 by volume) are eliminated; the following 16 fractions from the elution with pure methanol are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 2.9 g of product are thus obtained which is taken up in 57 cm3 of a 0.1N aqueous solution of hydrochloric acid. The cloudy solution obtained is brought to a pH close to 8 by addition of sodium bicarbonate and is then extracted 3 times with 750 cm3 in total of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 2.2 g of product are thus obtained which are redissolved in 43 cm3 of a 0.1N aqueous hydrochloric acid solution. The solution is then lyophilized. 2.1 g of (+) - N - {[α- (2-dimethylamino-ethoxyimino) benzyl] -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c hydrochloride are thus obtained. ] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of a pale yellow lyophilisate.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in the European patent application published under number 0 253,711.

The 2-dimethylaminoethoxyamine dihydrochloride can be obtained according to the method described D. FAVARA et al., Il Farmaco, Ed. Sci., 42 , 697 (1987).

EXAMPLE 8

To a solution of 3 g of (+) - N- (benzoyl-3 phenyl) (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 50 cm3 of propanol-1 heated to at a temperature in the region of 70 ° C., 1.6 g of 3-morpholino-propoxyamine dihydrochloride and 0.74 g of sodium carbonate are added, with stirring. The suspension obtained is heated to reflux for 8 hours then the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 4.7 g of crude product are thus obtained. This product is chromatographed on a column 5 cm in diameter containing 500 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and methanol (50-50 by volume) under a pressure of 0.5 bar (51 kPa), collecting 500 cm 3 fractions. The first 26 fractions are eliminated; the following 14 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The crude product obtained is taken up in 20 cm3 of ethanol. The suspension obtained is filtered and the filtrate obtained is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 1.08 g of product is thus obtained which is taken up in 9.3 cm3 of a 0.205N aqueous solution of methanesulfonic acid. The cloudy solution is filtered and the filtrate is lyophilized. 1.2 g of methanesulfonate of (+) - N - {[α- (3-morpholino-propoxyimino) benzyl] -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c are thus obtained ] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of a beige lyophilisate.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in the European patent application published under number 0 253,711.

The 3-morpholino-propoxyamine dihydrochloride can be obtained in the following manner: A solution of 13.8 g of N- (3-morpholino-propoxy) phthalimide in 50 cm 3 of 6N hydrochloric acid is heated at reflux for 6 hours. After 18 hours of agitation at a temperature in the region of 20 ° C, the suspension obtained is filtered and the filtrate obtained is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 6.8 g of crude product are thus obtained which are suspended in 10 cm3 of ethanol. The crystals which appear are separated by filtration and then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C. 6.1 g of 3-morpholino-propoxyamine dihydrochloride are thus obtained in the form of cream crystals, melting at 160 ° C.

The N- (3-morpholino-propoxy) phthalimide can be obtained as follows: A solution of 27.5 g of 3-morpholino-propanol, 30.2 g of N-hydroxy phthalimide and 47.2 g of triphenylphosphine in 400 cm3 of tetrahydrofuran is cooled to a temperature in the region of 0 ° C. and 37.65 g of ethyl azodicarboxylate are added over 1 hour and 30 minutes. The solution obtained is stirred at a temperature in the region of 20 ° C for 18 hours and then concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The residue is taken up in 500 cm3 of ethyl acetate and the suspension obtained is filtered. The filtrate is extracted with 200 cm3 of an aqueous solution of hydrochloric acid N. The aqueous phase is decanted and then extracted 3 times with 600 cm3 in total of ethyl acetate. The aqueous phase is brought to a pH in the region of 10 by addition of an aqueous sodium hydroxide solution and is extracted 3 times with 300 cm 3 in total of ethyl acetate. The organic extracts are combined, washed 3 times with 150 cm3 in total of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature 40 ° C. 25.8 g of crude product are thus obtained which are chromatographed on a column 8 cm in diameter containing 1 kg of silica (0.060 mm). Eluted with pure ethyl acetate, collecting 500 cm 3 fractions. The first 12 fractions are eliminated; the next 48 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 15.5 g of N- (3-morpholino-propoxy) phthalimide are thus obtained in the form of white crystals melting at 98C.

Morpholino-3 propanol can be obtained according to O. HROMATKA, Ber., 75 , 131, (1942).

EXAMPLE 9

To a solution of 4.7 g of (+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 85 cm3 of propanol-1 heated to a temperature in the region of 70 ° C., 3 g of (4-methyl-piperazinyl-1) -2-ethoxyamine hydrochloride and 1.8 g of sodium carbonate are added, with stirring. The suspension obtained is heated to reflux for 10 hours then the reaction mixture is concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in 100 cm3 of an aqueous hydrochloric acid solution N. The solution obtained is extracted 3 times with 150 cm3 in total of ethyl ether, brought to a pH close to 7 by addition of an aqueous solution saturated with sodium bicarbonate and extracted 3 times with 300 cm3 in total of ethyl ether. The ethereal extracts are combined, washed with 100 cm3 of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C . This gives 3.1 g of crude product which is chromatographed on a column 5 cm in diameter containing 300 g of silica (0.02-0.045 mm). Eluted with a mixture of acetonitrile and ammonia (d = 0.92) (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 200 cm3. The first 10 fractions are eliminated. The following 2 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.55 g of product are thus obtained. This product is redissolved in 5 cm3 of acetone. The solution obtained is added, at a temperature in the region of 20 ° C, to a solution of 0.46 g of oxalic acid in 10 cm 3 of acetone. The suspension obtained is stirred at a temperature in the region of 20 ° C for 30 minutes, then the crystals which appear are separated by filtration, washed twice with 5 cm 3 in total of acetone, dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. 1.7 g of (+) - N - {{α - [(4-methyl-piperazinyl-1) -2 ethoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H acid dioxalate are thus obtained. -pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of white crystals melting at 172 ° C.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in the European patent application published under number 0 253,711.

The (4-methyl-piperazinyl-1) -2 ethoxyamine hydrochloride can be obtained according to the method described by R. CRICCHIO et al., J. Med. Chem., 17 , 396 (1974).

EXAMPLE 10

To a solution of 3 g of (+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 50 cm3 of propanol-1 heated to at a temperature in the region of 70 ° C., 2.1 g of (methyl-1 piperidyl-4) oxyamine dihydrochloride, in the dihydrochloride form, and 0.72 g of sodium carbonate are added. The suspension obtained is heated to a temperature in the region of 90 ° C for 2 hours and 30 minutes, then is stirred at a temperature in the region of 20 ° C for 18 hours and finally filtered. The filtrate is concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 35 ° C. 6.1 g of crude product are thus obtained which is taken up in 60 cm3 of acetonitrile. The crystals obtained are separated by filtration and taken up in a mixture of 50 cm3 of sodium hydroxide and 20 cm3 of ethyl acetate. The organic phase is decanted and the aqueous phase is extracted twice with 40 cm3 in total of ethyl acetate. The organic extracts are combined, washed 3 times with a total of 45 cm 3 of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature. 35 ° C. The 3.2 g of product obtained are chromatographed on a column 4 cm in diameter containing 35 g of silica (0.02-0.045 mm). Eluted with 200 cm3 of a mixture of ethyl acetate and methanol (60-30 by volume). The fraction obtained is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 35 ° C. 1.25 g of product are thus obtained which is redissolved in 5 cm3 of ethyl acetate. 0.42 cm 3 of a 5.6N solution of hydrochloric gas in ethyl ether is then added to the solution. The crystals that appear are separated by filtration and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C. 0.82 g of product is thus obtained which is redissolved in 20 cm3 of distilled water. The solution obtained is brought to a pH close to 10 by addition of an aqueous 2N sodium hydroxide solution and is then extracted 3 times with 30 cm 3 in total of ethyl acetate. The organic extracts are combined, washed twice with 20 cm 3 in total of distilled water, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature. 40 ° C. The 0.65 g obtained are combined with 0.55 g of product obtained previously according to the same method and are chromatographed on a column 4 cm in diameter containing 300 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting 500 cm 3 fractions. The first 7 fractions are eliminated. The following 5 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 880 mg of product are thus obtained which is dissolved in 16.4 cm3 of an aqueous 0.1N hydrochloric acid solution. The solution obtained is extracted twice with 40 cm3 in total of ethyl ether and the phase aqueous solution is brought to a pH close to 10 by addition of an aqueous sodium hydroxide solution N and is then extracted 3 times with 60 cm 3 in total of ethyl acetate. The organic extracts are combined, washed twice with 20 cm 3 in total of distilled water, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature. 40 ° C. 630 mg of product are thus obtained. 530 mg of this product are dissolved in 5 cm3 of acetone. The solution obtained is added to a solution of 0.17 g of oxalic acid in 5 cm3 of acetone. The crystals which appear are separated by filtration, washed with 2 cm3 of acetone and then with 2 cm3 of a mixture of acetone and ether. ethyl (50-50 by volume), and finally dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. There is thus obtained 570 mg of acid dioxalate of (+) - N - {{α - [(1-methyl-piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1 , 2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of cream crystals, melting at 170 ° C.

1.0 g of (+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1.2 -c] thiazolecarboxamide-7, in base form, in 4 cm3 of absolute ethanol. 0.93 cm3 of 4N hydrochloric ether is added to the solution obtained and diluted with 20 cm3 of ethyl acetate and then 100 cm3 of diethyl ether. After 15 hours of stirring at a temperature in the region of 20 ° C, the crystals which appear are separated by filtration, washed 4 times with 20 cm 3 in total of diethyl ether and air-dried at a temperature in the region of 20 ° C. 1.1 g of (+) - N - {{α - [(methyl-1 piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo hydrochloride are thus obtained. 1,2-c] thiazolecarboxamide-7, in the mixture of forms E and Z, in the form of cream crystals melting at 200-205 ° C.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained according to the method described in the European patent application published under No. 0 253 711.

The (1-methyl-4-piperidyl-4) oxyamine hydrochloride can be obtained in the following way: An aqueous solution of 18.7 g of N- (1-methyl-piperidinyl-4 oxy) phthalimide in 100 is refluxed for 3 hours cm3 of an aqueous solution of 6N hydrochloric acid. The suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The product obtained is suspended in 100 cm3 of ethanol and the crystals which appear are separated by filtration, washed twice with 100 cm3 in total of ethanol and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. 11.2 g of (methyl-1 piperidyl-4) oxyamine dihydrochloride are thus obtained in the form of white crystals, melting at 220 ° C.

The N- (1-methyl-4-piperidyl-oxy) phthalimide can be obtained in the following manner: From a suspension of 30.6 g of 4-hydroxy-1-methyl-piperidine, of 43.7 g of N-hydroxyphthalimide and of 68.3 g of triphenyl phosphine in 450 cm3 of tetrahydrofuran, 53.8 g of diethyl azodicarboxylate are added over 90 minutes, at a temperature close to 0 ° C. The suspension obtained is stirred at a temperature in the region of 20 ° C for 18 hours and then the reaction mixture is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The product obtained is taken up in 500 cm3 of ethyl acetate and the suspension obtained is filtered. The filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The product obtained is redissolved in 500 cm3 of an aqueous solution of hydrochloric acid N. The suspension obtained is filtered and the filtrate is extracted 3 times with 300 cm3 in total of ethyl ether, brought to a pH close to 10 by addition of 500 cm3 of an aqueous solution of sodium hydroxide N. The crystals which appear are separated by filtration, washed 3 times with 300 cm3 in total of distilled water and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. 19 g of N- (methyl-1 piperidyl-4 oxy) phthalimide are thus obtained in the form of beige crystals, melting at 90 ° C.

EXAMPLE 11

To a solution of 3 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 15 cm3 of anhydrous N, N-dimethylformamide, 0.36 g of a 50% dispersion of sodium hydride in oil is added at room temperature, under a stream of nitrogen and with stirring petroleum jelly. A solution of 2.61 g of (benzyl ethylamino) -3 propanol para-toluenesulfonate is then added in 13 cm3 of anhydrous N, N-dimethylformamide in approximately 5 minutes, then the solution is stirred for 12 hours at a temperature in the region of 20 °. vs. 250 cm3 of distilled water are then added and the solution is extracted 3 times with 240 cm3 in total of ethyl acetate. Organic extracts are combined, washed with 80 cm3 of an aqueous 0.1N hydrochloric acid solution. The aqueous phase is then brought to pH 8 by addition of a 1N aqueous sodium hydroxide solution and the solution is extracted 3 times with 240 cm 3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 1.61 g of a pasty brown residue are thus obtained. This product is chromatographed on a column 4 cm in diameter containing 200 g of neutral alumina (0.032-0.063 mm). Eluted with 2.8 liters of ethyl acetate and then with 750 cm3 of a mixture of ethyl acetate and methanol (95-5 by volume) under a pressure of 0.5 bar (51 kPa) in collecting fractions of 50 cm3. The first 27 fractions are eliminated. The following 39 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1 g of product is thus obtained which is dissolved in 5 cm 3 of ethyl acetate. 0.1 g of bleaching black is added, then filtered hot and the filter is rinsed with 5 cm 3 of ethyl acetate. To this solution, 0.8 cm 3 of a 4N solution of hydrochloric gas in ethyl ether is added and the mixture is stirred at a temperature in the region of 20 ° C for 15 minutes. The crystals obtained are separated by filtration, washed 4 times with 50 cm 3 in total of ethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. 0.96 g of (+) - N - {{α - [(benzyl ethylamino) -3 propoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo hydrochloride is thus obtained. 2-c] thiazolecarboxamide-7, in the form of a mixture of forms E and Z, in the form of cream crystals melting at 175 ° C.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in the European patent application published under number 0 253,711.

(Benzyl ethylamino) -3 propanol tosylate can be prepared as follows: To a solution of 3.86 g of (benzyl ethylamino) -3 propanol in 10 cm3 of pyridine, it is added, with stirring, in about 20 minutes , at 20 ° C, a solution of 3.8 g of para-toluenesulfonyl chloride in 10 cm3 of pyridine and the reaction mixture is stirred for 20 minutes at a temperature in the region of 20 ° C. 200 cm3 of distilled water are added to the solution, then it is extracted twice with 160 cm3 in total of ethyl acetate. The organic extracts are combined, washed with 200 cm3 in total of distilled water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C. 4.78 g of (benzyl ethylamino) -3 propanol paratoluenesulfonate are obtained, in the form of an orange oil used crude in the subsequent syntheses.

(Benzyl ethylamino) -3 propanol can be prepared as follows: A solution of 6.76 g of benzyl ethylamine, 6.15 cm3 of 3-chloro propyl acetate and 5.3 g of sodium carbonate in 25 cm3 of propanol-2 is heated to reflux, with stirring for 48 hours, then cooled to a temperature in the region of 20 ° C. The sodium chloride formed is separated by filtration and the solvent is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 17.4 g of an orange oil are obtained which is taken up in 30 cm3 of distilled water and 30 cm3 of an aqueous 10N hydrochloric acid solution. The solution obtained is heated for 6 hours at reflux and then cooled to a temperature in the region of 20 ° C. 200 mg of bleaching black are added. The solution is filtered and the filter is rinsed with a total of 50 cm3 of distilled water. 40 cm3 of ammonia (d = 0.92) are added and extracted 3 times with 240 cm3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The residue is distilled under reduced pressure. 5.38 g of N-ethyl N- (3-acetoxypropyl) benzylamine are thus obtained boiling at 95 ° C. under 0.2 mm of mercury (13.4 Pa).

EXAMPLE 12

0.62 g of a suspension containing 50% sodium hydride in petroleum jelly, a solution of 4 g of N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H is added under nitrogen and over 45 minutes, at a temperature close to 20 ° C. , 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 40 cm3 of anhydrous N, N-dimethylformamide. To the solution obtained is added over 40 minutes, at a temperature in the region of 18 ° C, a solution of 1.77 g of N- (2-chloro-ethyl) morpholine dihydrochloride in 40 cm3 of anhydrous N, N-dimethylformamide. The suspension obtained is stirred at a temperature in the region of 20 ° C for 18 hours. 0.21 g of a 50% suspension of sodium hydride in vaseline oil is then added, followed by 0.85 g of N- (2-chloro-ethyl) morpholine hydrochloride. The suspension obtained is heated to a temperature in the region of 65 ° C for 20 hours and then, after cooling to a temperature in the region of 20 ° C, is added 650 cm3 of distilled water and extracted 3 times with 300 cm3 in total of acetate ethyl. The organic extracts are combined, extracted with 100 cm3 of an aqueous 0.1N hydrochloric acid solution and the aqueous phase is extracted twice with 100 cm3 in total of ethyl ether. The aqueous phase is brought to a pH in the region of 10 by addition of an aqueous sodium hydroxide solution N and extracted 3 times with 300 cm 3 of ethyl acetate. The organic extracts are combined, washed 3 times with 150 cm3 in total of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature 30 ° C. 5 g of product are obtained which is chromatographed on a column 5 cm in diameter containing 600 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and methanol (90-10 by volume) under a pressure of 0.5 bar (51 kPa), collecting 500 cm3 fractions. The first 8 fractions are eliminated. The following 32 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 3 g of product are thus obtained which are redissolved in 30 cm3 of ethyl acetate. To the solution obtained is added 1.95 cm3 of a 5.6 N solution of hydrochloric gas in ethyl ether. The crystals which appear are separated by filtration, washed twice with 10 cm 3 in total of ethyl acetate and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 20 ° C. The 2.8 g of product obtained are dissolved in 30 cm3 of distilled water and the resulting solution is brought to a pH close to 10 by addition of an aqueous solution of sodium hydroxide N, extracted 3 times with 60 cm3 of acetate d 'ethyl. The organic extracts are combined, washed twice with 20 cm 3 in total of distilled water, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a similar temperature. 35 ° C. 1.77 g of product are thus obtained. This product is dissolved in 23.2 cm3 of an aqueous 0.13N hydrochloric acid solution and the solution obtained is lyophilized. 1.64 g of N - {{α - [(2-morpholino ethoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 ( mixture of forms E and Z), in the form of a cream lyophilisate.

N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) can be obtained as follows : To a solution of 23 g of N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 in 270 cm3 of propanol-1 heated to a neighboring temperature at 70 ° C., 7.5 g of hydroxylamine hydrochloride and 5.7 g of sodium carbonate are added. The suspension obtained is heated to reflux for 3 hours and stirred at a temperature in the region of 20 ° C for 18 hours. The crystals which appear are separated by filtration, washed 3 times with 150 cm 3 in total of distilled water and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C. 8.3 g of N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) are thus obtained. , in the form of cream crystals melting at 210 ° C.

N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 can be obtained according to the method described in the European patent application published under No. 0 253,711.

EXAMPLE 13

To a solution of 1.63 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 16 cm3 of anhydrous N, N-dimethylformamide, 0.22 g of a 50% dispersion of sodium hydride in water is added at room temperature, under a stream of nitrogen and with stirring petrolatum oil. Then a solution of 0.9 g of (2-chloro-ethyl) -4-benzyl-4-piperazine dihydrochloride in 5 cm3 of anhydrous N, N-dimethylformamide is added in approximately 5 minutes. The solution is then stirred for 20 hours at room temperature and concentrated to dryness under reduced pressure (20 mm of mercury 2.7 kPa) at a temperature in the region of 40 ° C. The pasty residue is triturated in 40 cm3 of acetone, the sodium chloride formed is separated by filtration and washed with 15 cm3 in total of acetone and the filtat is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C. 3.1 g of a pasty orange residue are thus obtained. This product is chromatographed on a column 3 cm in diameter containing 65 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting 90 cm3 fractions. The first 15 fractions are eliminated; the following 19 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.45 g of product are thus obtained. This product is dissolved in 5 cm3 of ethyl acetate. 10 cm3 of ethyl ether and 2 cm3 of a 4 N solution of hydrochloric gas in ethyl ether are added to the solution obtained, then diluted with 20 cm3 of ethyl ether and stirred at a temperature in the region of 20 ° C for 15 minutes. The crystals obtained are separated by filtration and washed 4 times with 40 cm 3 in total of ethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 1.5 g of (+) - N - {{α - [(4-benzyl-1-piperazinyl-1) -2 ethoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H- dihydrochloride are thus obtained. pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of white crystals melting at 186 ° C.

(+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

Benzyl-1 (2-chloro-ethyl-1)) -4 piperazine dihydrochloride can be obtained according to the method described by DC KRIESEL, O. GRISVOLD, J. Pharm. Sci., 56 , 325 (1967).

EXAMPLE 14

To a solution of 3.0 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 22 cm3 of anhydrous N, N-dimethylformamide, 0.68 g of sodium hydride (at 50% dispersion in water) is added at room temperature, under a stream of nitrogen and with stirring petrolatum oil). After 15 minutes of stirring at room temperature, 0.9 g of (2-chloro-ethyl) methylamine hydrochloride is added and stirring at room temperature is maintained for 15 hours then the reaction medium is poured into 250 cm3 of water distilled. After 1 hour of stirring at room temperature, the solid is separated by filtration, washed with distilled water until neutral then dissolved in 16 cm3 of ethyl acetate and filtered. 1.57 cm3 of 4.1N hydrochloric ether are then added and after 1 hour with stirring at room temperature, the crystals are separated by filtration, washed with 6 cm3 of ethyl acetate and 40 cm3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. The hydrochloride obtained (3.04 g) is dissolved in 30 cm3 of distilled water, 6 cm3 of 1N sodium hydroxide are added and the mixture is extracted twice with 40 cm3 in total of ethyl acetate. The organic extracts are combined, washed with 15 cm 3 of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. An ocher meringue (2.4 g) is obtained which is chromatographed on a column 4 cm in diameter containing approximately 150 g of silica (0.02-0.045 mm). Eluted with a mixture of acetonitrile and ammonia (d = 0.92) (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting 80 cm3 fractions. The first 14 fractions are eliminated. The following 3 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 45 ° C. 1.47 g of product are thus obtained. This product is dissolved in 9 cm3 of ethyl acetate, treated with 0.2 g of bleaching black, filtered and added with 1.50 cm3 of 4N hydrochloric ether and then 15 cm3 of diethyl ether. The crystals which appear are separated by filtration, washed with a total of 15 cm 3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 40 ° C. 1.6 g of (+) - N - {[α- (2-methylamino-ethoxyimino) benzyl] -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c hydrochloride are thus obtained ] thiazolecarboxamide-7, as a mixture of forms E and Z, in the form of white crystals melting at 150-155 ° C.

(+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) is obtained as described in Example 1.

EXAMPLE 15

To a solution of 1 g of (+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2 -c] thiazolecarboxamide-7, (mixture of forms E and Z), in 20 cm3 of 100% acetic acid, 3.8 cm3 of a 1N ethanolic solution of methanesulfonic acid are successively added, then 0.2 cm3 30% hydrogen peroxide (110 volumes); stirring at room temperature is maintained for 15 hours and the solvent is concentrated under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 30 ° C. The residue is dissolved in 25 cm3 of distilled water, basified with 8 cm3 of sodium hydroxide (d = 1.33) and diluted with 15 cm3 of acetone and 30 cm3 of ethyl acetate; the organic phase is decanted, the aqueous phase is extracted with 30 cm3 of ethyl acetate. The organic extracts are combined, washed twice with 40 cm3 in total of distilled water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 45 ° C. 814 mg of a pink meringue are thus obtained. This product is chromatographed on a column 3 cm in diameter containing 50 g of approximately silica (0.02-0.045 mm). Eluted with a mixture of acetonitrile and ammonia (d = 0.92) (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 25 cm3. The first 10 fractions are eliminated. The following 4 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 430 mg of product are thus obtained. This product is dissolved in 3 cm3 of ethyl acetate, treated with 100 mg of bleaching black, filtered and rinsed with 1.5 cm3 in total of ethyl acetate. 0.47 cm3 of 3.25N hydrochloric ether is added to the solution obtained and stirred at a temperature in the region of 20 ° C for 30 minutes. 9 cm3 of diethyl ether are added and stirring is continued for an additional 1 hour at room temperature, then the crystals are separated by filtration and washed with 10 cm3 in total of diethyl ether and air-dried at a temperature in the region of 20 ° C. 460 mg of (+) - N - {{α - [(methyl-1 piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo hydrochloride are thus obtained 460 mg 2-c] thiazolecarboxamide-7 oxide-2- (2RS, 3R), as a mixture of forms E and Z, melting at 200 ° C.

(+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 , in the mixed state of forms E and Z, can be prepared as in Example 10.

EXAMPLE 16

A solution of 4.24 g of (+) - N - {{α - [(tert-butyloxy-carbonyl-4 piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H -pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 100 cm3 of ethyl acetate is stirred, in the presence of 8 cm3 of 3.2N hydrochloric ether, for 5 hours at temperature ambient then is filtered. The solid obtained, washed with 10 cm3 of diethyl ether and 15 cm3 of ethyl acetate is then dissolved in 50 cm3 of a 10% solution of sodium carbonate and extracted 3 times with 150 cm3 in total of dichloromethane. The organic extracts are washed with 50 cm3 of brine at 250 g / l, dried over sulphate anhydrous magnesium and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). The 3.6 g obtained are suspended in 50 cm3 of diethyl ether, added with 25 cm3 of 3N hydrochloric ether, diluted with 20 cm3 of ethyl acetate and stirred for 4 hours and thirty minutes at room temperature. The crystals which appear are separated by filtration, washed with 20 cm3 of diethyl ether, then dissolved in 50 cm3 of distilled water, basified to pH 9 with a 10% solution of sodium carbonate, and extracted with 450 cm3 in total of dichloromethane. The organic phases are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 2.7 g of a pink meringue are thus obtained. This product is chromatographed on a column 1.8 cm in diameter containing 50 g of neutral alumina (0.032-0.063 mm) deactivated with 10% water. Eluted with a mixture of ethyl acetate and methanol (80-20 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 20 cm3. The first 3 fractions are eliminated. The following 17 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.82 g of a beige meringue are thus obtained, which, added with 0.4 g from another operation, is chromatographed a second time on a column 1.4 cm in diameter containing 20 g of neutral alumina (0.032 -0.063 mm) deactivated by 10% water. Eluted with 300 cm3 of ethyl acetate, 180 cm3 of a mixture of ethyl acetate and methanol (95-5 by volume), 180 cm3 of a mixture 90-10 and 400 cm3 of a mixture of ethyl acetate and methanol 80-20, under a pressure of 0.5 bar (51 kPa), collecting fractions of 100 cm3. The first fraction is eliminated. The following 10 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.7 g of product are obtained which is dissolved in 20 cm 3 of ethyl acetate. To this solution is added 0.7 cm3 of 3.05N hydrochloric ether and stirred at a temperature in the region of 20 ° C for 10 minutes. The crystals obtained are separated by filtration, washed with 10 cm3 of ethyl acetate and 10 cm3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. 0.6 g of (+) - N - {{α - [(piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo dihydrochloride is thus obtained , 2-c] thiazolecarboxamide-7, in the mixture of forms E and Z, melting at 195 ° C.

(+) - N - {{α - [(tert-butyloxycarbonyl-4 piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c ] thiazolecarboxamide-7 (mixture of forms E and Z) can be prepared as follows: to a solution of 5.5 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 50 cm3 of anhydrous N, N-dimethylformamide, added at room temperature under a stream of nitrogen and under stirring, 0.56 g of sodium hydride (dispersed at 60 in vaseline oil). After 1 hour and 25 minutes of stirring at room temperature, a solution of 6.25 g of (tert-butoxycarbonyl-4 piperazinyl-1) -3-propyl paratoluenesulfonate in 25 cm3 of anhydrous N, N-dimethylformamide is introduced in 5 about minutes. Stirring is continued for 19 hours at room temperature and the solvent is evaporated to dryness under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 45 ° C. The residue is suspended in 100 cm3 of ethyl acetate at room temperature; the insoluble material is separated by filtration, washed with 40 cm3 of ethyl acetate and the filtrate is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 35 ° C. The residue (13.5 g) is chromatographed on a column 3.5 cm in diameter containing 250 g of neutral alumina (0.032-0.063 mm) deactivated with 10% water. Eluted with a mixture of ethyl acetate and cyclohexane (80-20 by volume) under a pressure of 0.5 bar (51 kPa), collecting 50 cm 3 fractions. The first 2 fractions are eliminated. The following 2 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 7.1 g of product are thus obtained which are rechromatographed a second time on a 2.7 cm diameter column containing 150 g of neutral alumina (0.032-0.063 mm) deactivated with 10% water. Eluted with a mixture of ethyl acetate and cyclohexane (50-50 by volume). The 4 first fractions are eliminated. The following 7 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 4.4 g of (+) - N - {{α - [(tert-butyloxycarbonyl-4 piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H- are thus obtained. pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of an orange oil.

The (tert-butoxycarbonyl-4 piperazinyl-1) -3-propyl paratoluenesulfonate can be prepared as follows: a solution of 11.6 g of paratoluenesulfonyl chloride in 50 cm3 of pyridine is added over 1 hour and 50 minutes solution of 13.5 g of (3-hydroxypropyl) -1 tert-butoxycarbonyl-4 piperazine in 50 cm3 of pyridine cooled to 0 ° C and stirred for 15 hours at a temperature in the region of 20 ° C. The temperature is brought to 10-15 ° C., 8.5 cm3 of triethylamine are introduced, then 170 cm3 of distilled water and 170 cm3 of ethyl acetate. The organic phase is decanted, the aqueous phase is extracted with 300 cm3 in total of ethyl acetate. The organic extracts are combined, washed with 750 cm3 of distilled water, dried over anhydrous magnesium sulfate, treated with 0.2 g of bleaching black, filtered and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa ) at a temperature close to 45 ° C. 16.3 g of (tert-butoxycarbonyl-4 piperazinyl-1) -3-propyl paratoluenesulfonate are thus obtained in the form of a red oil.

(3-Hydroxy propyl) -1 tert-butoxycarbonyl-4 piperazine can be prepared as follows: a solution of 12 g of di-tert-butyldicarbonate in 100 cm3 of dichloromethane is added to a solution of 7.2 g (3-hydroxypropyl) -1 piperazine in 100 cm3 of dichloromethane; stirring is continued for 24 hours at room temperature and the solvent is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 13.8 g of (3-hydroxypropyl) -1 tert-butoxycarbonyl-4 piperazine are thus obtained, in the form of a yellow oil. (Rf = 0.25, chromatography on a thin layer of silica, eluent: ethyl acetate).

EXAMPLE 17

A solution of 0.5 g of (+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 2,2-dioxide and 0 , 23 g of (methyl-1 piperidyl-4) oxyamine in the dihydrochloride state, in 10 cm 3 of pyridine is heated at reflux for 4 hours. 0.12 g of (methyl-1 piperidyl-4) oxyamine dihydrochloride is added and the reflux is continued for 1 hour. The mixture is cooled to a temperature in the region of 20 ° C, the solvent is concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) to a temperature in the region of 45 ° C, the residue is diluted in 30 cm3 of water distilled and added with 3.4 cm3 of 1N sodium hydroxide. The crystals which appear are separated by filtration, washed with 20 cm 3 in total of distilled water and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. The beige powder obtained (0.59 g) is dissolved in 4 cm3 of acetone. The solution is filtered, with the addition of 2.5 cm3 of ethyl acetate and then 0.49 cm3 of 4.1N hydrochloric ether. After 15 minutes of stirring at room temperature, the crystals which have appeared are separated by filtration, washed with 15 cm 3 in total of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a similar temperature 60 ° C. The dihydrochloride (590 mg), dissolved in 10 cm3 of distilled water is basified with 2 cm3 of 1N sodium hydroxide, then the crystals are separated by filtration, washed with distilled water until neutral and dried under reduced pressure (0, 1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. The solid (416 mg) is dissolved in 2 cm3 of absolute ethanol, treated with 10 mg of bleaching black, filtered, washed with 6 cm3 of ethyl acetate and added with 0.36 cm3 of hydrochloric ether 3, 65N. After 15 hours of stirring at room temperature, the crystals are separated by filtration, washed with 30 cm3 in total of diethyl ether and air dried. 470 mg of N- {α - [(1 methyl-4 piperidyl-4) oxyiminobenzyl] -3 phenyl} (3-pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 dihydrochloride are thus obtained. , dioxide-2,2- (3RS) in the state of mixture of forms E and Z, in the form of cream crystals, melting at 200 ° C.

(+) - N- (3-benzoylphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 dioxide-2,2 is obtained according to the method described in the European patent application published under No. 0 253 711.

(1-Methyl-piperidyl-4) oxyamine dihydrochloride can be obtained as described in Example 10.

EXAMPLE 18

To a solution of 1.74 g of (+) - N - {[α-hydroxyimino (4-methoxy benzyl)] - 3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 17.5 cm3 of anhydrous N, N-dimethylformamide, 0.18 g of sodium hydride is added at room temperature under nitrogen flow and with stirring 50% dispersion in petrolatum oil). After 30 minutes of stirring at room temperature, a solution of 2.61 g of (3-chloro-propyl) -1 4-methyl-piperazine in 2 cm3 of anhydrous N, N-dimethylformamide is introduced in approximately 5 minutes, then the solution is stirred for 15 hours at a temperature in the region of 20 ° C. The solvent is concentrated under reduced pressure (0.5 mm of mercury; 67.5 Pa) at a temperature in the region of 50 ° C, then 25 cm3 of distilled water are added and crystallization is initiated. After 3 hours of stirring at room temperature, the crystals are separated by filtration, washed with distilled water until neutral and air dried. The 2.30 g of solid obtained is then dissolved in 40 cm3 of ethyl acetate and 37 cm3 of 0.1N hydrochloric acid are added. The aqueous phase is decanted, washed with 20 cm3 of ethyl acetate, basified with 3.7 cm3 of 1N sodium hydroxide and extracted with 40 cm3 of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, treated with 50 mg of bleaching black, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 1.41 g of a pale yellow meringue are thus obtained which is dissolved in 10 cm3 of ethyl acetate, filtered, rinsed with 8 cm3 in total of ethyl acetate and added with 1.5 cm3 of ether hydrochloric 3N. The mixture is stirred at a temperature in the region of 20 ° C. for 1 hour. The crystals that appear are separated by filtration, washed 3 times with 12 cm 3 in total of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. 1.53 g of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] (4-methoxybenzyl)} - 3 phenyl} (pyridyl-3) hydrochloride are thus obtained. 3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, in the mixture of forms E and Z, in the form of cream crystals melting at 170 ° C.

(+) - N- {α- [hydroxyimino (4-methoxy-benzyl)] - 3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) can be prepared as follows: to a suspension of 1.82 g of (+) - N - [(4-methoxy-benzoyl) -3 phenyl] (3-pyridyl) -3 1H, 3H-pyrrolo [ 1,2-c] thiazolecarboxamide-7 in 22 cm3 of propanol-1, 425 mg of sodium carbonate and 280 mg of hydroxylamine hydrochloride are added. The suspension is heated to reflux, with stirring for 2 hours. The solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C; the residue is diluted in 25 cm3 of distilled water and crystallization is initiated. The crystals are separated by filtration, washed with distilled water until neutral and air dried. 1.80 g of (+) - N- {α- [hydroxyimino (4-methoxy-benzyl)] - 3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide are thus obtained. -7 (mixture of forms E and Z), in the form of white crystals melting at 235 ° C.

(+) - N - [(4-methoxybenzoyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is prepared according to the method described in the application for European patent published under number 0 253 711.

EXAMPLE 19

To a solution of 480 mg of (+) - N- [α- (hydroxyiminobenzyl) -3 chloro-6 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture forms E and Z) in 5 cm3 of anhydrous N, N-dimethylformamide, 9 mg of sodium hydride are added at room temperature, with nitrogen flowing and with stirring 60% dispersion in petrolatum oil). After 40 minutes of stirring at room temperature, 190 mg of (2-chloro-ethyl) -4 morpholine are added and the solution is stirred for 23 hours at a temperature in the region of 20 ° C. 23 mg of sodium hydride (60% dispersion in petroleum jelly oil) and 43 mg of (2-chloro-ethyl) -4 morpholine are added and stirring is continued for 24 hours at a temperature in the region of 20 ° C. The solvent is concentrated under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. 15 cm3 of ethyl acetate are added. The sodium chloride is separated by filtration and washed with 20 cm 3 of ethyl acetate. After evaporation of the solvent under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C, the residue (660 mg) is chromatographed on a column 1.4 cm in diameter containing 20 g of basic alumina (0.050-0.200 mm). Eluted with ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting 5 cm3 fractions. The first 8 fractions are eliminated. The following 58 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 370 mg of product are thus obtained which is dissolved in 10 cm3 of ethyl acetate and added with 0.42 cm3 of 3N hydrochloric ether. The mixture is stirred at a temperature in the region of 20 ° C. for 10 minutes and the crystals which appear are separated by filtration, washed with 5 cm 3 of ethyl acetate and 10 cm 3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 25 ° C. 388 mg of (+) - N - {{α - [(2-morpholino-ethoxyimino] benzyl} -3 chloro-6 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2 hydrochloride are thus obtained. -c] thiazolecarboxamide-7, as a mixture of forms E and Z, in the form of cream crystals melting at 154 ° C.

(+) - N - [(α-hydroxyiminobenzyl) -3 chloro-6 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) can be prepared as follows: to a suspension of 490 mg of (+) - N- [3-benzoyl-6-chloro-phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide -7 in 5.5 cm3 of propanol-1, 113 mg of sodium carbonate and 150 mg of hydroxylamine hydrochloride. The suspension is heated to reflux, with stirring for 2 hours and the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The residue is diluted in 40 cm3 of distilled water and crystallization is initiated. The crystals are separated by filtration, washed with 20 cm3 of distilled water and air dried. 490 mg of (+) - N - [(α-hydroxyiminobenzyl) -3-chloro-6 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of white crystals melting at 135 ° C.

(+) - N- [3-benzoyl-6-chloro-phenyl] (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is prepared according to the method described in the European patent application published under No. 0 253 711.

EXAMPLE 20

To a solution of 2.02 g of (+) - N - {[hydroxyimino (2-pyridyl-2) methyl] -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide- 7 (mixture of forms E and Z) in 20 cm3 of anhydrous N, N-dimethylformamide, 220 mg of sodium hydride (at 50% dispersion in l 'vaseline oil). After 25 minutes of stirring at a temperature in the region of 20 ° C., a solution of 813 mg of (3-chloro-propyl) -1 4-methyl-piperazine in 2 cm 3 of anhydrous N, N-dimethylformamide is introduced in approximately 5 minutes, then the solution is stirred for 21 hours at room temperature. The solvent is concentrated under reduced pressure (0.5 mm of mercury; 67.5 Pa) at a temperature in the region of 50 ° C, then 40 cm3 of distilled water and 40 cm3 of ethyl acetate are added. The organic phase is decanted and the aqueous phase is extracted with 40 cm3 of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, treated with 50 mg of bleaching black, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 2.32 g of a beige meringue are thus obtained, which is dissolved in 23 cm3 of ethyl acetate. The solution is filtered, rinsed with 8 cm3 of ethyl acetate and added with 2.6 cm3 of 3N hydrochloric ether. After 1 hour of stirring at room temperature, the crystals which appear are separated by filtration, washed 3 times with 12 cm 3 in total of ethyl acetate and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 50 ° C. The dihydrochloride (2.29 g) is dissolved in 40 cm3 of distilled water basified with 4 cm3 of 2N sodium hydroxide. After adding 30 cm3 of acetone to dissolve, 40 cm3 of ethyl acetate and 40 cm3 of distilled water are added. The organic phase is decanted, the aqueous phase is extracted with 40 cm3 of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The beige meringue obtained (1.74 g) is dissolved in 10 cm3 of ethyl acetate. The solution is filtered, washed with 7.5 cm3 of ethyl acetate and added with 1.87 cm3 of 3N hydrochloric ether. The crystals which appear are separated by filtration, washed with 15 cm 3 of ethyl acetate and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. 1.65 g of (+) - N - {{[(4-methyl-piperazinyl-1) -3 propoxyimino] (2-pyridyl) methyl} -3 phenyl} (3-pyridyl) -3 1H, 3H- are obtained. pyrrolo [1,2-c] thiazolecarboxamide-7, in the mixture of forms E and Z, in the form of cream crystals melting at 180 ° C.

(+) - N - {[hydroxyimino (2-pyridyl-methyl)] -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z ) can be prepared as follows: to a suspension of 2.13 g of (+) - N - [(2-pyridyl carbonyl) -3 phenyl] (3-pyridyl) -3 1H, 3H-pyrrolo [1, 2-c] thiazolecarboxamide-7 in 26 cm3 of propanol-1, 530 mg of sodium carbonate and 350 mg of hydroxylamine hydrochloride are added. The suspension is heated to reflux, with stirring, for 1 hour and the solvent is evaporated under reduced pressure (0.5 mm of mercury; 67.5 Pa) at a temperature in the region of 50 ° C, then the residue is diluted in 25 cm3 distilled water and crystallization is initiated. After 24 hours of stirring at room temperature, the crystals are separated by filtration, washed with distilled water until neutral and air dried. 2.11 g of (+) - N - {[hydroxyimino (2-pyridyl) methyl] -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 are thus obtained (mixture of forms E and Z) in the form of white crystals melting at 150-160 ° C.

(+) - N - [(pyridyl-2) carbonyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is prepared according to the method described in the application European patent published under No. 0 253 711.

EXAMPLE 21

A suspension of 1 g of (+) - N - {{α - [(piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c ] thiazolecarboxamide-7 (mixture of forms E and Z), 134 mg of potassium carbonate and 0.134 cm3 of 2-bromo ethanol in 20 cm3 of acetonitrile is stirred at a temperature in the region of 20 ° C for 24 hours. The insoluble material is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 1.13 g of a yellow oil are obtained which is chromatographed on a column 1.7 cm in diameter containing 50 g of neutral alumina (0.032-0.063 mm) deactivated with 10% water. Eluted with a mixture of ethyl acetate and methanol (80-20 by volume) under a pressure of 0.5 bar (51 kPa), collecting 25 cm3 fractions. The first 2 fractions are eliminated. The following 2 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The yellow meringue (800 mg) obtained is chromatographed a second time on a 1.4 cm diameter column containing 25 g of neutral alumina deactivated at 10% water (0.032-0.063 mm). Eluted with a mixture of ethyl acetate and methanol (90-10 by volume) under a pressure of 0.5 bar (51 kPa), collecting 15 cm 3 fractions. The first 5 fractions are eliminated. The following 7 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The 465 mg of product obtained are dissolved in 5 cm3 of ethyl acetate and added with 0.51 cm3 of 3N hydrochloric ether. After 15 minutes of stirring at a temperature in the region of 20 ° C., the crystals which appear are separated by filtration, washed with 2 cm 3 of ethyl acetate and 5 cm 3 of diethyl ether and dried under reduced pressure (0.1 mm mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 460 mg of (+) - N - {{{α - [(2-hydroxyethyl) -4 piperazinyl-1] -3 propoxyimino} benzyl} -3 phenyl} (pyridyl-3) -3 1H hydrochloride are thus obtained. , 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, as a mixture of forms E and Z, in the form of white crystals melting at 178 ° C.

Le (+) - N - {{α - [(pipérazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 ( mixture of forms E and Z) is obtained as described in Example 16.

EXAMPLE 22

A suspension of 3.11 g of (+) - N - {{{α- [N- (2-chloroethyl) anilino] -2 ethoxyimino} benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H -pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), 680 mg of methylamine hydrochloride, 2.07 g of potassium carbonate, 950 mg of copper iodide in 62 cm3 of acetonitrile is heated in an autoclave for 6 hours at 100 ° C. The insoluble material is filtered, rinsed 3 times with 60 cm 3 in total of acetonitrile. The filtrate is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 1.30 g of a green lacquer are obtained. Furthermore, the solid is suspended in 300 cm3 of ammonia (d = 0.92), 300 cm3 of ethyl acetate are added and the organic phase is decanted, washed with 200 cm3 of distilled water, dried on anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 45 ° C. The residue is diluted in 20 cm3 of ethyl acetate; 20 cm3 of 0.5N hydrochloric acid are added, the aqueous phase is decanted, basified with 2.2 cm3 of 5N sodium hydroxide and extracted with 40 cm3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. We obtain 1.15 g of an ocher meringue, which added with the 1.3 g of green lacquer previously obtained is chromatographed on a column 3.5 cm in diameter containing about 125 g of silica (0.02-0.045 mm). Eluted with a mixture of acetonitrile and ammonia (d = 0.92) (95-5 by volume) under a pressure of 0.3 bar (30.6 kPa), collecting 80 cm3 fractions. The first 15 fractions are eliminated. The following 3 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 370 mg of a yellow meringue are thus obtained which is dissolved in 3.7 cm3 of ethyl acetate, filtered and the insoluble material is rinsed with 1.7 cm3 of ethyl acetate. 0.39 cm3 of 3N hydrochloric ether is added to the solution obtained and is stirred at a temperature in the region of 20 ° C for 15 minutes. The suspension is diluted with 20 cm3 of diethyl ether, stirred for 1 hour at a temperature in the region of 20 ° C and the crystals are separated by filtration, washed with 20 cm3 in total of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. 370 mg of (+) - N - {{{α- [N- (2-methylaminoethyl) anilino] -2-ethoxyimino} benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H dihydrochloride are thus obtained. -pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of yellowish crystals, melting at 150-155 ° C.

(+) - N - {{{α- [N- (2-chloroethyl) anilino] -2 ethoxyimino} benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2- c] thiazolecarboxamide-7 (mixture of forms E and Z) can be prepared as follows: to a suspension of 480 mg of sodium hydride (in 50% dispersion in petroleum jelly oil) in 10 cm3 of N , Anhydrous N-dimethylformamide, a solution of 4.4 g of (+) - N- [α- (hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) - is added under nitrogen flow over approximately 25 minutes. 3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 10 cm3 of anhydrous N, N-dimethylformamide. After 15 minutes of stirring at room temperature, a solution of 2.18 g of N, N-bis (2-chloroethyl) aniline in 10 cm3 of anhydrous N, N-dimethylformamide is introduced in approximately 2 minutes. The solution is then stirred for 16 hours at room temperature. The solvent is concentrated to dryness under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 45 ° C. The residue is suspended in 80 cm3 of distilled water. After 1 hour of stirring at a temperature in the region of 20 ° C., the crystals are separated by filtration, washed with 20 cm 3 in total of distilled water and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 20 ° C. 6.32 g of a residue are thus obtained which is chromatographed on a column 5.5 cm in diameter containing about 250 g of silica (0.02-0.045 mm). Eluted with ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting fractions of 100 cm3. The first 10 fractions are eliminated. The following 8 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 3.41 g of (+) - N - {{{α- [N- (2-chloroethyl) anilino] -2 ethoxyimino} benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H are thus obtained -pyrrolo [1,2-c] thiazolecarboxamide-7, (mixture of forms E and Z), in the form of a yellow meringue (Rf = 0.54, chromatography on a thin layer of silica; eluent: ethyl acetate) .

(+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) is obtained as described in Example 1.

EXAMPLE 23

To a solution of 4.18 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 40 cm3 of anhydrous N, N-dimethylformamide, 0.42 g of sodium hydride (at 60% dispersion in water) is added at room temperature, under a stream of nitrogen and with stirring petrolatum oil). The suspension is stirred for 1 hour at a temperature in the region of 20 ° C. then a solution of 3.27 g of quinuclidine-3- (3RS) paratoluenesulfonate in 25 cm3 of anhydrous N, N-dimethylformamide is then introduced in approximately 5 minutes. The solution is stirred for 18 hours at room temperature and then heated at 70 ° C for 6 hours. After bringing the temperature back to 20 ° C., the solvent is evaporated off under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 40 ° C. The residue is diluted in 40 cm3 of ethyl acetate; the insoluble material is filtered, washed with 20 cm3 of ethyl acetate and the filtrate is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 7.5 g of a pasty red residue are thus obtained. This product is chromatographed on a 2.4 cm diameter column containing 150 g of neutral alumina (0.050-0.200 mm). Eluted with a mixture of ethyl acetate and methanol (90-10 by volume), collecting fractions of 100 cm3. The first 12 fractions are eliminated. The following 4 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The 3.34 g of product obtained are chromatographed a second time on a column 1.9 cm in diameter containing 60 g of alumina (0.050-0.200 mm). Eluted with 1000 cm3 of ethyl acetate and 1000 cm3 of a mixture of ethyl acetate and methanol (90-10 by volume), collecting 100 cm3 fractions. The first 10 fractions are eliminated. The following 10 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. This gives 0.97 g of an orange meringue which is chromatographed on a column 3 cm in diameter containing 65 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting 40 cm3 fractions. The first 21 fractions are eliminated. The following 19 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 0.64 g of product is thus obtained. This product is dissolved in 10 cm3 of ethyl acetate and added with 0.81 cm3 of 3N hydrochloric ether. After 10 minutes of stirring at room temperature, the crystals which appear are separated by filtration and washed with 20 cm3 of ethyl acetate and 20 cm3 in total of diethyl ether, and dried under reduced pressure (0.1 mm of mercury ; 13.5 Pa) at a temperature in the region of 50 ° C. 0.64 g of dihydrochloride of (+) - N - {{α - [(quinuclidinyl-3- (3RS) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo] is thus obtained 1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of a beige powder melting at 200 ° C.

The (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

Quinuclidine-3- (3RS) paratoluenesulfonate can be obtained in the following manner: 6.3 g of paratoluenesulfonyl chloride dissolved in a solution is added under a stream of nitrogen and with stirring, over approximately 1 hour and 30 minutes 15 cm3 of pyridine in a solution of 3.8 g of quinuclidinol-3- (3RS) in 15 cm3 of pyridine cooled to 0 ° C and stirred for 2 hours between 5 and 10 ° C, then 12 hours at a temperature close to 20 ° C. The temperature is brought back to 15 ° C. and 4.63 cm3 of triethylamine are added. The reaction medium is poured into 100 cm3 of distilled water. 100 cm3 of ethyl acetate are added; the aqueous phase is decanted and washed with 200 cm3 in total of ethyl acetate. The organic extracts are combined, washed twice with 200 cm3 in total of distilled water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 35 °. vs. 6.5 g of quinuclidine-3- (3RS) paratoluenesulfonate are thus obtained in the form of a red oil used as it is.

EXAMPLE 24

To a solution of 2.0 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 10 cm3 of anhydrous N, N-dimethylformamide, 220 mg of sodium hydride (50% dispersion) are added at a temperature in the region of 20 ° C., under a stream of nitrogen and with stirring in petroleum jelly). The suspension is stirred for 30 minutes at a temperature in the region of 20 ° C., cooled to 0 ° C., then a solution of 1.2 g of 1-methyl-piperidyl-3- (3RS) paratoluenesulfonate in 6 cm3 of N, N- anhydrous dimethylformamide is introduced in approximately 30 minutes. The solution, stirred for 2 hours at 0 ° C. and then 16 hours at room temperature, is then poured into 100 cm 3 of distilled water. The suspension is extracted 3 times with 150 cm3 in total of ethyl acetate and washed 2 times with 100 cm3 in total of distilled water. The organic phase is acidified with 50 cm3 of 0.1N hydrochloric acid, the aqueous phase is decanted and neutralized with 1.2 cm3 of 5N sodium hydroxide. Extracted twice with 50 cm3 of ethyl acetate, treated with 100 mg of bleaching black, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at temperature close to 45 ° C. 1.6 g of an ocher meringue are obtained, which is chromatographed on a 3.5 cm diameter column containing 125 g of silica (0.020-0.045 mm). Eluted with a mixture of acetonitrile and ammonia (d = 0.92) (97-3 by volume) under a pressure of 0.3 bar (21 kPa), collecting 80 cm3 fractions. The first 20 fractions are eliminated. The following 7 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 1.6 g of a pale yellow meringue are thus obtained. This product is dissolved in 6.6 cm3 of ethyl acetate, the solution is filtered, added with 1.4 cm3 of 3N hydrochloric ether and diluted with 20 cm3 of diethyl ether. After 30 minutes of stirring at room temperature, the crystals which have appeared are separated by filtration, washed with 20 cm 3 in total of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a similar temperature 50 ° C. 1.3 g of (+) - N - {{α - [(methyl-1 piperidyl-3- (3RS)) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H- are thus obtained. pyrrolo [1,2-c] thiazolecarboxamide-7- (3R) (mixture of forms E and Z), in the form of a yellow powder melting at 165-170 ° C.

The (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H- pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

The methyl-1 piperidyl-3- (3RS) paratoluenesulfonate can be obtained in the following manner: a solution of 9.5 g of paratoluenesulfonyl chloride in 25 cm3 of pyridine is added, with stirring, over approximately 30 minutes. solution of 5.8 g of methyl-1 piperidinol-3- (3RS) in 25 cm3 of pyridine cooled to 0 ° C and stirred for 2 hours between 5 and 10 ° C, then 12 hours at a temperature in the region of 20 ° C . 7.1 cm3 of triethylamine are added while maintaining the temperature around 20 ° C. The reaction medium is poured in 150 cm3 of distilled water. 150 cm3 of ethyl acetate are added; the aqueous phase is decanted and washed with 100 cm3 in total of ethyl acetate. The organic extracts are combined, washed twice with 80 cm3 in total of distilled water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 °. vs. 8.8 g of methyl-1 piperidyl-3- (3RS) paratoluenesulfonate are thus obtained in the form of a red oil [Rf = 0.72, chromatography on a thin layer of silica; eluent: acetonitrile-ammonia (d = 0.92) (95-5 by volume)].

EXAMPLE 25

To a solution of 2.2 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 20 cm3 of anhydrous N, N-dimethylformamide, 0.29 g of sodium hydride (at 50% dispersion in water) is added at room temperature, under a stream of nitrogen and with stirring. petrolatum oil). After 45 minutes of stirring at room temperature, a solution of 0.75 g of N, N-diethylchloroacetamide in 5 cm3 of anhydrous N, N-dimethylformamide is introduced in approximately 1 minute, stirring at room temperature being maintained for 15 hours then the solvent is concentrated to dryness under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 60 ° C. The residue is diluted in 30 cm3 of acetone, the insoluble material is filtered and washed twice with 20 cm3 in total of acetone. The filtrate is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 3.4 g of an orange product are obtained which is chromatographed on a column 3 cm in diameter containing about 150 g of silica (0.02-0.045 mm). Eluted with ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting 30 cm3 fractions. The first 18 fractions are eliminated. The following 13 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45C. The 2.15 g of product obtained are dissolved in 6 cm 3 of acetonitrile and 2.9 cm 3 of 4N hydrochloric ether are added. After 15 minutes of stirring at room temperature, the crystals which appear are separated by filtration, washed twice with 20 cm 3 in total of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 20 ° C. 2 g of (+) - N - {[α- (diethylcarbamoylmethoxyimino) benzyl] -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 dihydrochloride are thus obtained. as a mixture of forms E and Z, in the form of white crystals melting at 135 ° C.

(+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) is obtained as described in Example 1.

EXAMPLE 26

To a solution of 2.2 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 20 cm3 of anhydrous N, N-dimethylformamide, 0.5 g of sodium hydride (at 60% dispersion in water) is added at room temperature, under a stream of nitrogen and with stirring petrolatum oil). The suspension is stirred for 1 hour at room temperature and then 0.72 g of (2-chloro-ethyl) -4 morpholine hydrochloride is added. After 15 hours of stirring at room temperature, the solvent is evaporated to dryness under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 45 ° C. 3.8 g of a pasty orange residue are thus obtained. This product is chromatographed on a column 3 cm in diameter containing approximately 65 g of silica (0.02-0.045 mm). Eluted with ethyl acetate, under a pressure of 0.5 bar (51 kPa), collecting 50 cm 3 fractions. The first 7 fractions are eliminated. The following 43 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The residue (1.8 g) is chromatographed a second time on a column 3 cm in diameter containing 65 g of silica (0.02-0.045 mm). Eluted with ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting fractions of 150 cm3. The first 15 fractions are eliminated. The following 21 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The meringue obtained (1.4 g) is dissolved in 40 cm3 of ethyl acetate and 2 cm3 of 4N hydrochloric ether are added. The crystals which have appeared are separated by filtration, washed successively with 15 cm 3 of ethyl acetate and with 20 cm 3 of diethyl ether, and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a similar temperature. 60 ° C. The white residue obtained (1.4 g) is dissolved in 10 cm3 of distilled water. After adding 10 cm3 of a 10% sodium carbonate solution, the solution is extracted 3 times with 50 cm3 in total of ethyl acetate. The organic extracts are combined, washed with 40 cm3 of distilled water, dried over anhydrous magnesium sulfate, treated with 0.2 g of bleaching black, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 35 ° C. 0.95 g of a pale yellow meringue are thus obtained which is chromatographed on a column 1.7 cm in diameter containing 30 g of neutral alumina deactivated at 10% water (0.032-0.063 mm). Eluted with 200 cm3 of ethyl acetate and 210 cm3 of a mixture of ethyl acetate and methanol 95-5 (by volume), under a pressure of 0.5 bar (51 kPa), collecting fractions of 10 cm3. The first 21 fractions are eliminated. The following 25 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The residue (0.55 g) is dissolved in 2 cm3 of ethyl acetate. 0.58 cm3 of 3.9N hydrochloric ether, 2 cm3 of ethyl acetate and 5 cm3 of diethyl ether are added to the solution obtained. After 5 minutes of stirring at a temperature in the region of 20 ° C., the crystals obtained are separated by filtration, washed with 2 cm3 of ethyl acetate and 5 cm3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature (close to 60 ° C.) This gives 0.58 g of (+) - N - {[α- (2-morpholino-ethoxyimino) benzyl] -3 phenyl} (pyridyl -3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, in the mixture of forms E and Z, in the form of dihydrochloride, melting at 163 ° C.

(+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

EXAMPLE 27

To a solution of 1 g of (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 7.4 cm3 of anhydrous N, N-dimethylformamide, 0.12 g of sodium hydride (at 50% dispersion in water) is added at room temperature, under a stream of nitrogen and with stirring. petrolatum oil). A solution of 0.67 g of 1-methyl-piperidyl-4-paratoluenesulfonate in 6.7 cm 3 of anhydrous N, N-dimethylformamide is then introduced in approximately 5 minutes. The solution is stirred for 15 hours at room temperature and then 0.14 g of methyl-1 piperidyl-4-paratoluenesulfonate is added and stirring is continued for an additional 3 hours. This operation is repeated 3 times and the reaction medium is diluted with 100 cm 3 of distilled water. After 15 minutes of stirring at room temperature, the solid is separated by filtration and washed twice with 40 cm 3 in total of distilled water. The residue is dissolved in 50 cm3 of ethyl acetate and 46 cm3 of 0.1N hydrochloric acid are added. The aqueous phase is decanted and basified with 5 cm3 of sodium hydroxide (d = 1.33). After two hours of stirring at room temperature, the crystals are separated by filtration and washed with 20 cm 3 in total of distilled water. 0.82 g of (+) - N - {{α - [(1-methyl-piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo are thus obtained 2-c] thiazolecarboxamide-7 (mixture of forms E and Z), in the form of a cream powder [Rf = 0.33; thin-layer chromotography ; eluent: acetonitrile-ammonia (d = 0.92) (95-5 by volume).

The (+) - N - [(α-hydroxyiminobenzyl) -3 phenyl] (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 is obtained as described in Example 1.

The methyl-1 piperidyl-4-paratoluenesulfonate can be obtained in the following manner: 19.60 g of paratoluenesulfonyl chloride are added over a solution of approximately 1 hour and 30 minutes. 11.50 g of 4-hydroxy-1-methylpiperidine in 50 cm3 of pyridine cooled to 0 ° C and stirred for 4 hours at 0 ° C, then 12 hours at a temperature in the region of 20 ° C. After adding 14.10 g of triethylamine and stirring for an additional 15 minutes, 300 cm3 of distilled water and 300 cm3 of ethyl acetate are added. The aqueous phase is decanted and washed with 200 cm3 of ethyl acetate. The organic extracts are combined, washed with a total of 500 cm3 of distilled water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. The last traces of pyridine are removed under a higher vacuum (0.1 mm of mercury; 13.5 Pa). 19.6 g of methyl-1 piperidyl-4 paratoluenesulfonate are thus obtained in the form of a brown oil. [Rf = 0.56; thin layer chromatography on silica; eluent: acetonitrile-ammonia (d = 0.92) (95-5 by volume).

EXAMPLE 28

3.3 g of chloroformyl-7 hydrochloride (3-pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole and then 2.3 cm3 of triethylamine are successively added over approximately 5 minutes, then 2.3 cm3 of triethylamine to a solution of 3.5 g of O - [(4-methyl-1-piperazinyl) -3 propyl] 3-amino benzophenone oxime Z in 45 cm3 of dichloromethane and the mixture is stirred at room temperature for 12 hours. After addition of 0.6 g of chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride and an additional 0.6 g of triethylamine, the solution is stirred again for 1 hour and the solvent is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 35 ° C. The residue is then supplemented with 50 cm3 of distilled water and 50 cm3 of ethyl acetate; the organic phase is decanted, washed with 35 cm3 in total of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The residue (6.6 g) is chromatographed on a column 6 cm in diameter containing approximately 400 g of silica (0.063-0,200 mm) using the following elution gradient: 280 cm3 of a mixture of acetonitrile and d 'ammonia (d = 0.92) 99-1 by volume; this fraction is eliminated; 350 cm3 of a 95-5 mixture and 280 cm3 of a 90-10 mixture of acetonitrile and ammonia. The last two fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. The cream meringue obtained (4.6 g) is dissolved in 60 cm3 of ethyl acetate, treated with 0.5 g of bleaching black, filtered and added with 4.8 cm3 of 3.25N hydrochloric ether. After 30 minutes of stirring at room temperature, the crystals which appear are separated by filtration, washed with 100 cm 3 in total of ethyl acetate and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 50 ° C. 4.8 g of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H- dihydrochloride are thus obtained. pyrrolo [1,2-c] thiazolecarboxamide-7, form B, melting at 168 ° C.

Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 115,979.

O - [(4-methyl-1-piperazinyl) -3 propyl] 3-amino benzophenone oxime Z can be prepared as follows: a solution of 5 g of 3-amino benzophenone oxime Z in 35 cm3 of N , Anhydrous N-dimethylformamide is added over about 15 minutes to a suspension of 1.14 g of sodium hydride (in 50% dispersion in petroleum jelly oil) in 35 cm3 of anhydrous N, N-dimethylformamide. The medium is stirred for 15 minutes at room temperature and a solution of 4.17 g of (3-chloro-propyl) -1 4-methyl-piperazine in 35 cm3 of anhydrous N, N-dimethylformamide is introduced in 5 minutes at a similar temperature. 2 ° C. After 12 hours of stirring at room temperature, the solvent is evaporated to dryness under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. The residue is diluted in 50 cm3 of ethyl acetate, the mineral salts are filtered, washed with 50 cm3 in total of ethyl acetate and the filtrates are concentrated to dryness under reduced pressure (20 mm of mercury; 2, 7 kPa) at a temperature close to 45 ° C. This gives 9.2 g of O - [(4-methyl-1-piperazinyl) -3 propyl] 3-amino benzophenone-oxime Z in the form of an orange oil [Rf = 0.23; chromatography on thin layer of eluting silica: ethyl acetate-diethylamine (95-5 by volume)].

The 3-amino benzophenone oxime Z can be prepared as follows: heating for 4 hours at reflux 600 cm 3 of a pyridine solution of 32 g of 3-amino benzophenone and 22.6 g of hydrochloride hydroxylamine, then the solvent is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 50 ° C. The residue is then diluted with 400 cm3 of distilled water and crystallization is initiated. After 2 hours of stirring at room temperature, the crystals are separated by filtration and washed with 1 liter in total of distilled water. 35.4 g of 3-amino benzophenone oxime (mixture of forms E and Z) are thus obtained in the form of a beige powder. 3 fractions of 11.8 g were chromatographed on a column 7 cm in diameter containing 600 g of silica (0.02-0.045 mm) with a mixture of methylene chloride and ethyl acetate (80-20 in volumes) under a pressure of 0.5 bar (51 kPa) and collecting 100 cm3 fractions. The first 19 fractions are eliminated. The next 8 fractions corresponding to form Z are combined, the following 13, mixture of forms E and Z are eliminated and the last 26 are combined to form a batch enriched in form E. The two batches are concentrated to dryness under reduced pressure ( 20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C. 11.2 and 9.5 g are obtained respectively. The two products are each resuspended in 50 cm3 of diisopropyl ether, the crystals are separated by filtration, washed with 20 cm3 in total of diisopropyl ether and dried under reduced pressure (20 mm of mercury; 2.7 kPa ) at a temperature close to 20 ° C. 10.43 g of 3-amino benzophenone-oxime Z are thus obtained, and 5.7 g of a mixture enriched to 80% with 3-amino-benzophenone-oxime E which will be used as it is.

EXAMPLE 29

3.5 g of chloroformyl-7 hydrochloride (3-pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole and then 3.0 cm3 of triethylamine are successively added over about 5 minutes. 2.9 g O - [(4-methyl-1-piperazinyl) -3 propyl] 3-amino benzophenone oxime form E (80% pure) in 30 cm3 of dichloromethane and the mixture is stirred at room temperature for 1 hour and 30 minutes. After addition of an additional 0.25 g of chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride, the solution is again stirred for 2 hours and 15 minutes, then diluted per 30 cm3 of distilled water. The organic phase is decanted, washed with a total of 60 cm3 of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa). The 4.1 g of beige meringue obtained are chromatographed on a column 6 cm in diameter containing about 400 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 100 cm3. The first 25 fractions are eliminated. The following 30 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 2.9 g of meringue are obtained which are suspended in 120 cm3 of ethyl acetate and are heated to reflux until complete dissolution, then cooled to 25 ° C. To this solution, 3.0 cm3 of 3.25M hydrochloric ether is added and the mixture is stirred at a temperature in the region of 5 ° C for 30 minutes. The crystals obtained are separated by filtration, washed with 25 cm3 of ethyl acetate and 50 cm3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 °. vs. 2.6 g of (+) - N - {{α - [(4-methyl-piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H- dihydrochloride are thus obtained. pyrrolo [1,2-c] thiazolecarboxamide-7, form A, melting at 160 ° C.

Chloroformyl-7 (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared according to the method described in European Patent No. 0 115 979.

O - [(4-methyl-1-piperazinyl) -3 propyl] 3-amino benzophenone oxime E can be prepared as follows: to a solution of 3.2 g of 3-amino benzophenone oxime E in 20 cm3 of anhydrous N, N-dimethylformamide, 0.7 g of sodium hydride is added at room temperature, under a stream of nitrogen and with stirring. 60% dispersion in petrolatum oil). The mixture is stirred for 1 hour and then a solution of 2.7 g of (3-chloro-propyl) -1 4-methyl-piperazine in 20 cm 3 of anhydrous N, N-dimethylformamide is introduced in approximately 15 minutes. After 1 hour and 15 minutes of stirring at room temperature, the solvent is evaporated to dryness under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 50 ° C. The residue is taken up in 50 cm3 of ethyl acetate; the mineral salts are removed by filtration, washed with 50 cm3 of ethyl acetate and the solvent is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 35 ° C. The residue is diluted in 40 cm3 of ethyl acetate and extracted 3 times with 40 cm3 in total of 1N hydrochloric acid then the aqueous phases are combined, brought to pH 8 with 2N sodium hydroxide and the solution is extracted 2 times per 50 cm3 in total of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The 4.5 g of orange oil obtained are chromatographed on a column 6 cm in diameter containing about 500 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa) and collecting 80 cm3 fractions. The first 16 fractions are eliminated. The following 16 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 3.8 g of O - [(methyl-4 piperazinyl-1) -3 propyl] -3-amino-benzophenone-oxime E are thus obtained in the form of an orange oil [Rf = 0.32, thin layer chromatography of silica; eluent: ethyl acetate-diethylamine (95-5 by volume)].

The 3-amino benzophenone oxime enriched to 80% in E form is obtained as described above.

EXAMPLE 30

1 g of (+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide -7, in the mixed state of forms E and Z is chromatographed on a column 4 cm in diameter containing approximately 100 g of silica (0.02-0.045 mm). Eluted with a mixture of diethyl ether and diethylamine (85-15 by volume) under a pressure of 0.2 bar (20 kPa), collecting fractions of 25 cm3. The first 20 fractions are eliminated. The next 11 fractions corresponding to the first form of eluted oxime, called form A are combined, as well as the following 15 fractions, corresponding to a mixture enriched to 70% in the second form of oxime called form B. After evaporation of the solvent under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C, 0.4 g of form A and 0.6 g of a mixture enriched in form B are obtained.

EXAMPLE 31

Form A (0.4 g) is dissolved in 1 cm3 of absolute ethanol, filtered and then successively added with 0.9 cm3 of 0.4N hydrochloric ether, 3 cm3 of ethyl acetate, 0.9 cm3 d hydrochloric ether 0.4N and 5 cm3 of diethyl ether. After 3 hours of stirring at room temperature, the crystals which appear are separated by filtration and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 0.18 g of (+) - N - {{α - [(methyl-1 piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo hydrochloride is obtained. , 2-c] thiazolecarboxamide-7, form A, melting at 175-180 ° C.

EXAMPLE 32

The product enriched to 70% in form B (0.6 g) is chromatographed a second time on a column 4 cm in diameter containing about 150 g of silica (0.02-0.045 mm). Eluted with a mixture of diethyl ether and diethylamine (85-15 by volume) under a pressure of 0.2 bar (20 kPa), collecting fractions of 25 cm3. The first 20 fractions are eliminated. The following 18 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. We obtain thus 0.39 g of pure form B which is dissolved in 2 cm3 of absolute ethanol, treated with 0.1 g of bleaching black, filtered and added with 2 cm3 of absolute ethanol and 10 cm3 of ethyl acetate . 0.18 cm 3 of 4N hydrochloric ether is then added, with stirring, and after 1 hour at room temperature, the crystals are separated by filtration and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) to a temperature close to 20 ° C. 0.31 g of (+) - N - {{α - [(methyl-1 piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo hydrochloride is obtained. , 2-c] thiazolecarboxamide-7, form B, melting at 264 ° C.

EXAMPLE 33

11.8 g of (+) - N - {{α - [(1-methyl-piperidyl-4) oxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1.2 -c] thiazolecarboxamide-7 (mixture of forms E and Z) in 55 cm3 of absolute ethanol and 6 cm3 of 3.65M hydrochloric ether are added. After 2 hours of stirring at room temperature, the crystals are separated by filtration and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 8.0 g of monohydrochloride of a product enriched to 85% in form B are obtained. The filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 4.9 g of a brown oil enriched with 90% form A are obtained.

The solid (majority form B) is suspended in 100 cm 3 of absolute ethanol and heated under reflux for 5 minutes then the temperature is brought to 20 ° C. The crystals are separated by filtration and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 6.6 g of pure hydrochloride of form B are obtained. The filtrate, evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 40 ° C, leads to 3.7 g of a yellow meringue which will be used in the preparation of the oxime of form A. The 6.6 g of pure hydrochloride of form B are then added with 25 cm3 of acetone and then with 14 cm3 of 1N sodium hydroxide and are extracted with 50 cm3 at total ethyl acetate. The organic extracts are washed with distilled water until neutral, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 6.2 g of a white meringue are obtained. 7.4 g of 1M sulfuric ethanol are added to 4 g of the product dissolved in 140 cm3 of acetonitrile. After 15 minutes of stirring at room temperature, the crystals which appear are separated by filtration, washed with 20 cm3 of acetonitrile and 40 cm3 of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 20 ° C. 3.5 g of (+) - N - {{α - [(1-methyl-piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo are thus obtained 2-c] thiazolecarboxamide-7, form B, in the form of acid sulphate melting at 145 ° C.

Furthermore, the 4.9 g of oil obtained (90% form A) is taken up in 35 cm3 of acetone and added with 20 cm3 of 1N sodium hydroxide. The aqueous phase is extracted twice with 100 cm3 in total of ethyl acetate. The organic extracts are combined, washed with distilled water until neutral, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C . 4.85 g of a pasty orange residue are thus obtained. This product is chromatographed on a column 6 cm in diameter containing approximately 500 g of silica (0.02-0.045 mm). Eluted with a mixture of diethyl ether and diethylamine (85-15 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 100 cm3. The first 33 fractions are eliminated. The following 19 fractions composed of pure form A are combined in a single batch; the last 17 enriched in form A form a second batch. The solvent is evaporated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 2.0 g of pure form A and 1.5 g are thus obtained in which A is the majority.

These 1.5 g and the 3.7 g of meringue obtained previously during the purification of form B are combined and chromatographed on a 4 cm column containing 150 g of silica (0.043-0.063 mm). Eluted with a mixture of diethyl ether and diethylamine (88-12 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 100 cm3. The first 46 fractions are eliminated. The following 20 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 2.5 g of pure form A are thus obtained.

This batch and the 2 g already obtained are dissolved in 40 cm3 of ethyl acetate, treated with 0.2 g of bleaching black. After filtration, the solution is added with 4.1 cm3 of 3.65N hydrochloric ether and is stirred at a temperature in the region of 20 ° C for 15 minutes. The crystals are separated by filtration, washed successively with 20 cm3 of ethyl acetate and 20 cm3 in total of diethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature close to 20 ° C. 4.1 g of (+) - N - {{α - [(1-methyl-piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo are thus obtained 2-c] thiazolecarboxamide-7, form A, in the form of dihydrochloride, melting at 166 ° C.

EXAMPLE 34

To a solution of 4.1 g of O- (methyl-1 piperidyl-4) 3-amino benzophenone-oxime Z in 50 cm3 of dichloromethane, is added, with stirring 4.8 g of chloroformyl-7 hydrochloride (pyridyl- 3) -3 1H, 3H-pyrrolo [1,2-c] thiazole and 4.5 cm3 of triethylamine. The suspension is stirred for 15 hours at room temperature, then 0.48 g of chloroformyl-7 hydrochloride (3-pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazole is added. After one hour of stirring, 50 cm3 of distilled water are added and the organic phase is decanted and washed with 100 cm3 in total of distilled water. The organic extracts are dried over anhydrous magnesium sulphate, treated in the presence of bleaching black, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 6.8 g of a pasty orange residue are thus obtained. This product is chromatographed on a column 6 cm in diameter containing approximately 450 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 100 cm3. The first 16 fractions are eliminated. The following 24 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 4.4 g of product are thus obtained, in the form of a beige meringue which, added to 1.7 g from another operation, is chromatographed a second time on a column of 2.7 cm in diameter containing 80 g of silica (0.02-0.045 mm) approx. Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting 30 cm3 fractions. The first 15 fractions are eliminated. The following 35 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 5.5 g of a beige meringue are thus obtained which is dissolved in 120 cm3 of acetonitrile and 10.2 cm3 of 1M sulfuric ethanol are added. After 1 hour of stirring at room temperature, the crystals which appear are separated by filtration, washed with 50 cm 3 of ethyl ether and dried under reduced pressure (0.1 mm of mercury; 13.5 Pa) at a temperature in the region of 20 ° C. 5.9 g of (+) - N - {{α- [methyl-1 piperidyl-4) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo are obtained. c] thiazolecarboxamide-7, form B, in the form of acid sulfate melting at 153 ° C.

O- (1-methyl-4-piperidyl) 3-amino benzophenone oxime Z can be prepared as follows: to a solution of 3.48 g of 3-amino benzophenone oxime Z in 30 cm3 of N, N anhydrous dimethylformamide, 0.72 g of sodium hydride (60% dispersion in petroleum jelly) is added at room temperature under a stream of nitrogen and with stirring. The suspension is stirred at room temperature for 45 minutes and a solution of 5.4 g of 1-methyl-piperidyl-4-paratoluenesulfonate in 50 cm3 of anhydrous N, N-dimethylformamide is then introduced in approximately 15 minutes. The solution is then stirred for 1 hour and 20 minutes at room temperature then 0.2, 0.3 and 0.6 g of 1-methyl-piperidyl-4-paratoluenesulfonate are added at intervals of 1, 15 and 4 hours respectively. 0.14 g of sodium hydride (60% dispersion in petroleum jelly oil) is then added and a solution of 1.8 g of 1-methyl-piperidyl-4-paratoluenesulfonate in cm3 of N, N-dimethylformamide anhydrous. The solution is stirred for 15 hours at room temperature then 300 cm3 of distilled water are added and the solution is extracted 4 times with 400 cm3 in total of ethyl acetate. The organic extracts are combined, washed with 500 cm3 of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 45 ° C. 6.8 g of a pasty orange residue are thus obtained. This product is chromatographed on a column 6 cm in diameter containing approximately 500 g of silica (0.02-0.045 mm). Eluted with a mixture of ethyl acetate and diethylamine (95-5 by volume) under a pressure of 0.5 bar (51 kPa), collecting 80 cm3 fractions. The first 15 fractions are eliminated. The following 25 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 4.13 g of O- (methyl-1 piperidyl-4) amino-3 benzophenone-oxime Z are thus obtained in the form of a yellow oil.

The 3-amino benzophenone oxime Z can be prepared as in Example 28.

The methyl-1 piperidyl-4-paratoluenesulfonate can be prepared as described in Example 27.

The present invention also relates to medicaments consisting of a product of general formula (I), in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (especially in gelatin capsules or cachets) or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can also comprise substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, use may be made of water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or any other suitable organic solvent. .

These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the products according to the invention are particularly useful in the treatment of all pathological conditions under which PAF-acether can be implicated directly or indirectly, in particular allergic, inflammatory and digestive system conditions such as ulcers, colitis and intestinal lesions caused by radiation or endotoxin shock.

The doses depend on the desired effect and on the duration of the treatment. They are generally between 25 and 300 mg per day orally, intravenously or by inhalation for an adult in one or more doses. In general, the doctor will determine the dosage which he considers to be the most appropriate based on age, weight and any other factor specific to the subject to be treated.

• A - soit Z représente une liaison de valence et R₂ représente un atome d'hydrogène
• B- soit Z représente une liaison de valence et R₂ représente un radical quinuclidinyle ou pipéridyle-3 ou -4 dont l'atome d'azote est éventuellement substitué par un radical alcoyle contenant 1 à 4 atomes de carbone,
• C- soit Z représente un radical alcoylène contenant 1 à 4 atomes de carbone et R₂ représente un radical pipéridyle-2, -3 ou -4 dont l'atome d'azote est éventuellement substitué par un radical alcoyle contenant 1 à 4 atomes de carbone ou bien R₂ représente un radical
  
  dans lequel R₃ représente un atome d'hydrogène ou un radical alcoyle contenant 1 à 4 atomes de carbone ou phényle et R₄ représente un radical
  
  dans lequel n est un nombre entier compris entre 1 et 4 inclusivement et R₅ et R₆, identiques ou différents, représentent un atome d'hydrogène ou un radical alcoyle contenant 1 à 4 atomes de carbone ou bien R₂ représente un radical
  
  dans lequel R₅ et R₆, identiques ou différents, représentent un radical alcoyle contenant 1 à 4 atomes de carbone ou phénylalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone ou bien R₅ et R₆ forment ensemble avec l'atome d'azote auquel ils sont liés un cycle morpholine, pipéridine ou pipérazine dont le second atome d'atoe peut être éventuellement substitué par un radical alcoyle contenant 1 à 4 atomes de carbone, hydroxyalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone ou phénylalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone, leurs énantiomères, leurs diastéréoisomères et leurs isomères E et Z pris seuls ou en mélanges ainsi que leurs sels pharmaceutiquement acceptables.

Of very particular interest are the products of general formula (I) in which R₁ represents a hydrogen or halogen atom or an alkyloxy radical of which the alkyl part contains 1 to 4 carbon atoms, Ar represents a phenyl radical or pyridyle, p is 0, 1 or 2 and:

• A - either Z represents a valence bond and R₂ represents a hydrogen atom
• B- either Z represents a valence bond and R₂ represents a quinuclidinyl or piperidyl-3 or -4 radical whose nitrogen atom is optionally substituted by an alkyl radical containing 1 to 4 carbon atoms,
• C- either Z represents an alkylene radical containing 1 to 4 carbon atoms and R₂ represents a piperidyl radical 2, -3 or -4 in which the nitrogen atom is optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or R₂ represents a radical
  
  in which R₃ represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon or phenyl atoms and R₄ represents a radical
  
  in which n is an integer between 1 and 4 inclusive and R₅ and R₆, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or R₂ represents a radical
  
  in which R₅ and R₆, identical or different, represent an alkyl radical containing 1 to 4 carbon atoms or phenylalkyl in which the alkyl part contains 1 to 4 carbon atoms or else R₅ and R₆ form together with the nitrogen atom to which they are linked a morpholine, piperidine or piperazine ring in which the second atom of atoe may be optionally substituted by an alkyl radical containing 1 to 4 carbon atoms, hydroxyalkyl of which the alkyl part contains 1 to 4 carbon atoms or phenylalkyl of which the alkyl part contains 1 to 4 carbon atoms, their enantiomers, their diastereoisomers and their E and Z isomers taken alone or in mixtures as well as their pharmaceutically acceptable salts.

• (+)-N-{{α-[(méthyl-4 pipérazinyl-1)-3 propoxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{[α-(diméthylamino-2 éthoxyimino) benzyl]-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{[α-(morpholino-2 éthoxyimino) benzyl]-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{{α-[(méthyl-4 pipérazinyl-1)-2 éthoxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{{α-[(méthyl-1 pipéridyl-4) oxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{{α-[(méthyl-4 pipérazinyl-1)-3 propoxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, forme A ;
• (+)-N-{{α-[(méthyl-1 pipéridyl-4) oxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, forme B ;
• (+)-N-{{α-[(méthyl-1 pipéridyl-4) oxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N{{α-[(méthyl-1 pipéridyl-4) oxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7 oxyde-2 (2RS,3R), mélange des formes E et Z ;
• (+)-N-{{α-[(pipérazinyl-1)-3 propoxyimino] benzyl}-3 phényl) (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{{{α-[(hydroxy-2 éthyl)-4 pipérazinyl-1]-3 propoxyimino} benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7, mélange des formes E et Z ;
• (+)-N-{{α-[(méthyl-1 pipéridyl-3-(3RS)) oxyimino] benzyl}-3 phényl} (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] thiazolecarboxamide-7-(3R), mélange des formes E et Z.

The following products are more particularly interesting:

• (+) - N - {{α - [(4-methyl-1-piperazinyl) -3 propoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide- 7, mixture of forms E and Z;
• (+) - N - {[α- (2-dimethylamino ethoxyimino) benzyl] -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, mixture of forms E and Z;
• (+) - N - {[α- (2-morpholino ethoxyimino) benzyl] -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, mixture of forms E and Z;
• (+) - N - {{α - [(4-methyl-1-piperazinyl) -2 ethoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide- 7, mixture of forms E and Z;
• (+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, mixture of forms E and Z;
• (+) - N - {{α - [(4-methyl-1-piperazinyl) -3 propoxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide- 7, form A;
• (+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, form B;
• (+) - N - {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, mixture of forms E and Z;
• (+) - N {{α - [(1-methyl-4-piperidyl) oxyimino] benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 oxide- 2 (2RS, 3R), mixture of forms E and Z;
• (+) - N - {{α - [(piperazinyl-1) -3 propoxyimino] benzyl} -3 phenyl) (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7, mixture E and Z forms;
• (+) - N - {{{α - [(2-hydroxyethyl) -4 piperazinyl-1] -3 propoxyimino} benzyl} -3 phenyl} (pyridyl-3) -3 1H, 3H-pyrrolo [1,2 -c] thiazolecarboxamide-7, mixture of forms E and Z;
• (+) - N - {{α - [(1-methyl-piperidyl-3- (3RS)) oxyimino] benzyl} -3 phenyl} (3-pyridyl) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7- (3R), mixture of forms E and Z.

The following example illustrates a composition according to the invention.

EXAMPLE A

Injectable unit doses containing 25 mg of active product are prepared according to the usual technique by dissolving 366.79 mg of (+) - N - {[α- (2-morpholino ethoxyimino) benzyl] -3 phenyl} (pyridyl-) dimethanesulfonate 3) -3 1H, 3H-pyrrolo [1,2-c] thiazolecarboxamide-7 (mixture of forms E and Z) in 25 cm3 of distilled water and distributing the solution evenly in 10 identical ampoules.

Claims (6)

1. Process for preparing new 1H,3H-pyrrolo[1,2-c]thia- zole-7-carboxamide derivatives, characterized in that they correspond to the general formula:

   

   in which R₁ represents a hydrogen or halogen atom or an alkyl, alkyloxy, trifluoromethyl, amino, alkylamino, dialkylamino, hydroxy, cyano, phenyl or phenoxy radical, Ar represents a phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, thienyl, thieno[2,3-b]thien-2-yl or thieno[3,2-b]thien-2-yl, it being possible for these radicals optionally to bear one or more substituents selected from halogen atoms or alkyl, alkyloxy, trifluoromethyl, amino, alkylamino, dialkylamino, hydroxy or cyano radicals, p represents an integer equal to zero, one or two, and

   A- either Z represents a valency bond and R₂ represents a hydrogen atom,

   B- or Z represents a valency bond and R₂ represents a 2- or 4-pyridyl, 3-quinuclidinyl, 3-pyrrolidinyl or 3- or 4-piperidyl radical, it being possible for the latter two radicals to be optionally substituted on the nitrogen atom with an alkyl, hydroxyalkyl, phenyl or phenylalkyl radical,

   C- or Z represents an alkylene radical containing 1 to 4 carbon atoms and R₂ represents a 2-, 3- or 4-pyridyl, 3-quinuclidinyl, 2- or 3-pyrrolidinyl or 2-, 3- or 4-piperidyl radical, it being possible for the latter two radicals to be substituted on the nitrogen atom with an alkyl, hydroxyalkyl, phenyl or phenylalkyl radical, or alternatively R₂ represents a radical of general formula:

   

   in which:

   a) either R₃ and R₄, together with the nitrogen atom to which they are attached, form a piperazine ring optionally substituted on the second nitrogen atom with an alkyl, hydroxyalkyl, pyridyl, phenyl or phenylalkyl radical,

   b) or R₃ represents a hydrogen atom or an alkyl, phenyl or phenylalkyl radical or a radical of general formula:

   

   in which n represents an integer between 1 and 4 and R₅ and R₆, which may be identical or different, represent a hydrogen atom or an alkyl, phenyl or phenylalkyl radical, or alternatively R₅ and R₆, together with the nitrogen atom to which they are attached, form a morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine ring in which the second nitrogen atom can be optionally substituted with an alkyl, hydroxyalkyl, pyridyl, phenyl, phenylalkyl or phenylcarbonyl radical, and R₄ represents a radical of general formula (III) defined as above, on the understanding that the definitions of n, R₅ and R₆ in the symbols R₃ and R₄ can be identical or different,

   D- or Z represents an alkylene radical containing 1 to 4 carbon atoms and R₂ represents a radical of general formula:

   

   in which R₃, R₄, R₅ and R₆ are defined as above in C a) and b), on the understanding that the alkyl radicals and alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain, as well as the racemic products, the enantiomers due to the presence of an asymmetric carbon at the 3-position of the pyrrolothiazole ring, the mixtures of these enantiomers, the diastereoisomers, pure or mixed, due to the possible presence of another chiral centre, and the E and Z (also known as syn and anti) isomers and mixtures thereof originating from the presence of the oxime group C=NO-Z-R₂, and the pharma- ceutically acceptable salts, characterized in that a hydroxylamine of general formula:
   
           H₂NO-Z-R₂   (VI)
   
   in which Z and R₂ are defined as above, is reacted with a ketone of general formula:

   

   in which the symbols p, R₁ and Ar are defined as in above.
2. Process for preparing new derivatives as defined in claim 1 in the formula of which the symbols are defined as in claim 1 in B or in D, characterized in that a product of general formula:
   
           X-Z-R₂   (VIII)
   
   in which Z and R₂ are defined in claim 1 and X represents a halogen atom, is reacted with a product of general formula (I), defined as in claim 1 in A, i.e. a product of general formula:

   

   in which p, R₁ and Ar are defined as in claim 1.
3. Process for preparing new derivatives as defined in claim 1 in the formula of which p is equal to 0, characterized in that a product of general formula:

   

   in R or S form or mixtures thereof, is reacted with an oxime of general formula:

   

   in which Ar, Z, R₁ and R₂ are defined as in claim 1, in E or Z form or mixtures thereof.
4. Process for preparing new derivatives as defined in claim 1 in the formula of which p is equal to 1, characterized in that a new derivative as defined in claim 1 in the formula of which p is equal to 0 is oxidized.